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Management of fulminant ulcerative colitis by primary restorative proctocolectomy.

Severe acute ulcerative colitis unresponsive to medical management is characterized by multiple associated risk factors including anemia, hypoproteinemia, and high steroid requirements when urgent surgery is required. Current surgical options include use of primary ileal pouch-anal anastomosis (IPAA) vs. historic trends favoring colectomy with ileostomy. To evaluate the efficacy of primary IPAA in patients with severe colitis, we reviewed our own experience in 20 patients with this condition. Patients undergoing primary restorative proctocolectomy included 13 males and 7 females (mean age, 30.5 +/- 2.4 years). Exclusion criteria for primary reconstruction included septic patients and patients with associated medical conditions such as pulmonary or cardiovascular disease. History of ulcerative colitis averaged 3.1 +/- 1.1 years (range, 1 month to 19 years). Preoperative mean total serum protein concentration was 5.0 +/- 0.2 g/dl, and mean albumin concentration was 2.1 +/- 0.2 g/dl, reflecting disease severity. The average daily steroid requirement at the time of urgent colectomy was 58.0 +/- 4.4 mg of prednisone (or intravenous equivalent). Primary IPAA included 18 "W" reservoirs, 1 "S" reservoir, and 1 "J" reservoir. Major surgical complications included mild pancreatitis (10 percent), anastomotic leak (5 percent), adrenal insufficiency (15 percent), an upper gastrointestinal bleed (5 percent), and small bowel obstruction (15 percent). There were no deaths, and no patients developed pelvic sepsis or required IPAA removal. At three and twelve months, 24-hr stool frequency averaged 7.3 +/- 0.4 and 4.9 +/- 0.3, respectively. Overall day and night continence was excellent and not different from patients who underwent elective IPAA procedures for ulcerative colitis. Improved options such as primary IPAA may be safely used in selected patients requiring urgent surgery for severe or fulminant ulcerative colitis. Medical management should be abbreviated when disease control cannot be promptly achieved.

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Evaluation of Omeprazole Limited Sampling Strategies to Estimate Constitutive Cytochrome P450 2C19 Activity in Healthy Adults.

Limited sampling strategy (LSS) is a validated method to estimate pharmacokinetic (PK) parameters from a reduced number of samples. Omeprazole is used to phenotype in vivo cytochrome P450 (CYP) 2C19 activity. This study examined an LSS using 2 estimation methods to determine apparent oral clearance (CL/F) and thus CYP2C19 activity. Data from 7 previously published studies included healthy subjects receiving a single, oral dose of omeprazole with intensive PK sampling. CL/F was estimated using noncompartmental analysis (NCA) and population PK modeling. LSS was simulated by selecting the 1, 2, 4, and/or 6-hour postdose time points. Linear regression was performed to assess whether CL/F estimated from limited sampling could accurately predict CL/F from the full PK profile. Median CL/F was 23.7 L/h by NCA and 19.3 L/h by population PK modeling. In comparing the LSS NCA estimated versus observed CL/F, all evaluated linear regression models had unacceptable coefficients of determination (r, range: 0.14-0.81). With the population PK approach, 737 plasma concentrations (n = 71) and CYP2C19 genotype data were described with a 1-compartment structural model with mixed zero and first-order absorption and lag time. In comparing the population PK LSS estimated versus observed CL/F, all evaluated linear regression models had unacceptable r (range: 0.02-0.74). Post hoc comparison of CYP2C19 poor metabolizers versus CYP2C19 extensive metabolizers resulted in significantly lower CL/F in poor metabolizers versus extensive metabolizers. Omeprazole LSS performed poorly in estimating CL/F using 2 separate estimation approaches and does not seem to be a suitable method for determining CYP2C19 activity.

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Fixed-dose combination of indacaterol/glycopyrronium/mometasone furoate once-daily versus salmeterol/fluticasone twice-daily plus tiotropium once-daily in patients with uncontrolled asthma: A randomised, Phase IIIb, non-inferiority study (ARGON).

The efficacy and safety of once-daily (o.d.) fixed-dose combination of indacaterol (IND), glycopyrronium (GLY) and mometasone furoate (MF) via Breezhaler® versus concurrent administration of salmeterol/fluticasone (SAL/FLU) twice-daily (b.i.d.) via Accuhaler®+Tiotropium (TIO) o.d. via Respimat® was evaluated in patients with uncontrolled asthma. Patients (aged ≥18 years), symptomatic (Asthma Control Questionnaire [ACQ]-7 ≥1.5) despite treatment with long-acting β₂-agonist/inhaled corticosteroid medium- or high-dose, received IND/GLY/MF high- (150/50/160 μg) or medium-dose (150/50/80 μg) o.d. or SAL/FLU high-dose (50/500 μg) b.i.d.+Tio 5 μg o.d. for 24 weeks. The primary objective was to confirm the non-inferiority of either dose of IND/GLY/MF to SAL/FLU high dose + TIO in terms of Asthma Quality of Life Questionnaire (AQLQ). Additional endpoints: ACQ-7, lung function, health status (St George's Respiratory Questionnaire [SGRQ]), exacerbations, and safety after 24 weeks. IND/GLY/MF high- and medium-dose met the primary endpoint, confirming non-inferiority to SAL/FLU high dose + TIO for AQLQ (least square mean treatment difference [Δ]: 0.073 and -0.038, respectively; both p < 0.001). IND/GLY/MF high-dose improved ACQ-7 (Δ: -0.124; p = 0.004), trough FEV₁ (Δ: 96 mL; p < 0.001), peak expiratory flow (morning [Δ: 9.56 L/min; p = 0.005], evening [Δ: 9.15 L/min; p = 0.006]) and SGRQ (Δ: -2.00; p = 0.04) versus SAL/FLU high dose + TIO. Improvements in these endpoints were comparable for IND/GLY/MF medium-dose and SAL/FLU high dose + TIO. Adverse events were generally comparable across treatments. IND/GLY/MF high- and medium-dose o.d. via a single inhaler were non-inferior to SAL/FLU high-dose b.i.d. + TIO o.d. via two inhalers for AQLQ. IND/GLY/MF high-dose o.d. improved lung function, asthma control and health status versus SAL/FLU high dose + TIO, while IND/GLY/MF medium-dose had comparable efficacy but at a corresponding lower steroid dose.

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Changes in platelet P-selectin and in plasma C-reactive protein in acute atherosclerotic ischemic stroke treated with a loading dose of clopidogrel.

The surface expression of P-selectin on platelets contributes to the progression of inflammatory processes and thrombosis in atherothrombosis. In this study, we showed that the combination regimen of clopidogrel with aspirin could downregulate the P-selectin expression on platelets and the plasma concentration of C-reactive protein (CRP) in acute stage of atherosclerotic ischemic stroke. Patients with acute ischemic stroke (<24 hours) were randomized for 7 days to combined regimen of clopidogrel and aspirin (n = 24) or intravenous heparin with aspirin (n = 28). We measured the changes of National Institute of Health Stroke Scale (NIHSS) scores, CRP concentration, and surface expressions of P-selectin on platelets during 7 days. The combined regimen of clopidogrel and aspirin significantly reduced platelet P-selectin expression (93.6 +/- 16.6, p < 0.01) and plasma concentration of CRP (1.2 +/- 1.5 mg/dl, p < 0.01) after 7 days of stroke onset compared with the values (P-selectin; 115.5 +/- 20.7, CRP; 2.5 +/- 2.8 mg/dl) of initial 24 hr. Also, the clinical improvement, as measured by NIHSS score, was significant in the clopidogrel loading group at 7 days (6.2 +/- 5.5, p < 0.05) compared to the initial 24 hrs (10.1 +/- 7.6). Our results indicate that the combined regimen of clopidogrel and aspirin has beneficial effects on regulating platelet activation and inflammatory processes in acute atherosclerotic ischemic stroke. Thus, this combination regimen deserves further evaluation in clinical trial for the treatment of acute atherosclerotic ischemic stroke.

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Effect of venlafaxine dosage, valproic acid concentration, sex, and age on steady state dose-corrected concentrations of venlafaxine and O-desmethylvenlafaxine: A retrospective analysis of therapeutic drug monitoring data in a Chinese population.

This study aimed to investigate the influence of diagnosis, body weight, sex, age, smoking, formulations, and concomitant drugs on steady-state dose-corrected serum concentrations (C/D) of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV). A retrospective analysis of therapeutic drug monitoring (TDM) was carried out. Patients' demographic data, therapeutic regimens, and concentrations were collected. We included 91 verified samples from 80 patients. Females had by average 13% smaller body weight, 50% higher C/D of VEN, and VEN + ODV and 25% smaller ODV/VEN than males. Patients >60 years had by average 33-59% higher C/D levels of ODV and VEN + ODV than younger patients. The concomitant use of valproic acid caused an average 51% higher C/D of ODV and a 2.2-fold larger ODV/VEN, while clozapine was related with 40% smaller ratio of ODV/VEN and 38% lower C/D levels of ODV. Positive correlations were detected between valproic acid concentrations and the C/D of VEN and VEN + ODV. In a multiple linear regression analysis, variance in the C/D of VEN + ODV was partly attributed to the daily dose of VEN, sex, age and valproic acid concentration. Our results suggested daily dose of VEN, sex, age, and valproic acid as indicators for the C/D of VEN + ODV in Chinese patients. TDM as a valuable tool was suggested in elderly female patients and patients receiving polypharmacy.

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Effect of serotonergic antidepressant therapy on temperament and character scales in patients with chronic tension-type headache.

The purpose of the present study was to assess a group of patients with chronic tension-type headache (CTTH) and control subjects using the personality questionnaire proposed by Cloninger and to determine possible changes in the Temperament and Character Inventory (TCI) patterns of CTTH patients after therapy with serotonergic antidepressants. Forty-five patients with CTTH filled out the TCI and Beck Depression Inventory (BDI) before and after 4-month prophylactic therapy with serotonergic antidepressants. A total of 50 age-, sex- and education level-matched healthy subjects were selected as a control group. During the pretreatment period patients were found to have higher harm avoidance and lower self-directedness scores than healthy comparison subjects. During the post-treatment period, although harm avoidance scores decreased and self-directedness scores increased, harm avoidance scores were still significantly higher and self-directedness scores significantly lower in CTTH patients than in controls. After using BDI score and age as covariates at the post-treatment period, harm avoidance scores were still higher in patients with CTTH while self-directedness scores did not differ between CTTH patients and controls. These findings suggest state and trait dependence of harm avoidance, and strong state dependence of self-directedness scores in CTTH patients. When interpreting data regarding personality measured by the TCI in CTTH patients, the effects of depressive symptomatology should be taken into account.

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[The relation between lymphocyte profile in BALF and the course of sarcoidosis based on short term observation].

The aim of this study was to assess how the extent of the number and percentage of lymphocytes in BALF and also the CD4 to CD8 ratio can help to predict the short outcome in sarcoidosis. Material consisted of 74 patients, 39 men and 35 women in the age from 23 to 58 years. 11 patients had chest lesions in stage I, 43 in stage II and 20 in stage III. Clinical markers of activity (fever, erythema nodosum) were present in 22 cases. Extrathoracic lesion were present in 31 and abnormal pulmonary function in 30. In all patients BAL was done before treatment and lymphocyte count, percentage and CD4/CD8 ratio was calculated. 50 patients were treated with corticosteroids and 24 were observed without treatment. After 6-12 month of observation regression of sarcoid lesions was observed in 46 of 50 patients treated with corticosteroids and in 17 out of 24 patients observed without treatment. There were no differences in lymphocyte count and percentage in BALF and in the short term outcome between group treated with corticosteroids and without treatment. The patients in whom regression of lesions was observed have however significantly higher CD4/CD8 ratio than others.

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Bone mineral density, growth, and thyroid function in long-term survivors of pediatric Hodgkin's lymphoma treated with chemotherapy only.

The aim of this study was to investigate the long-term side effects of treatment for childhood Hodgkin's lymphoma with chemotherapy only on growth, bone mineral density (BMD), body composition, and thyroid function. A total of 88 patients (56 male, 32 female; 17.6-42.6 yr), treated for childhood Hodgkin's lymphoma from 1974-1998 with combination chemotherapy adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine or epirubicin, bleomycin, vinblastine, dacarbazine with or without mechlorethamine, oncovin (vincristine), procarbazine, and prednisone (MOPP) with the intention to avoid radiotherapy, participated in this study. Median follow-up was 15.5 yr (range 5.6-30.2). BMD of lumbar spine and total body (BMD-TB), and body composition were measured using dual-energy x-ray absorptiometry. Bone mineral apparent density of the lumbar spine was calculated to correct for bone size. Free T4 and TSH were measured. Men treated with MOPP had a significantly reduced height with normal body proportions. Women treated with MOPP had decreased BMD-TB and bone mineral apparent density of the lumbar spine as compared with healthy controls. Percent body fat was significantly increased in female patients treated without MOPP. Body mass index was significantly increased in male patients treated without MOPP, whereas lean body mass was normal in all patients. All patients, except one, treated with chemotherapy only had normal thyroid function. However, five patients who received additional radiation to the thyroid either had abnormal levels of TSH or free T4, or used thyroid hormones. Lean body mass was normal in all patients; thyroid function was normal in all but one patient. The use of MOPP leads to decreased height and increased body mass index in men and decreased BMD-TB in women.

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Efficacy predictors for metformin and clomiphene citrate treatment in anovulatory infertile patients with polycystic ovary syndrome.

To evaluate ovulation and pregnancy predictors in infertile polycystic ovary syndrome (PCOS) patients who received clomiphene citrate (CC) and metformin as first-line ovulation inductors. Prospective controlled study. Departments of Obstetrics and Gynecology, Universities Magna Graecia of Catanzaro and Federico II of Naples, Italy. Eighty infertile anovulatory PCOS patients allocated in two groups matched for body mass index (BMI) and age. Metformin (1700 mg/day for 6 months) or CC (50 mg/day, increasing doses up to 250 mg/day). Baseline clinical and biochemical parameters categorized according to interventions response. The BMI was statistically significantly lower in patients who ovulated under both treatments. Insulin sensitivity indexes were statistically significantly worse in patients who ovulated under metformin and statistically significantly better in patients who ovulated under CC. Androgen levels and free androgen index (FAI) were statistically significantly lower in ovulatory patients than in anovulatory ones who received CC. Age, BMI, infertility duration, and insulin sensitivity indexes were statistically significantly different between patients who achieved and those who did not achieve a pregnancy under both treatments. Androgens levels and FAI were statistically significantly lower in patients who achieved a pregnancy under CC. Insulin-resistant PCOS patients with low BMI are more likely to respond to metformin whereas CC treatment is more effective in less hyperandrogenic and insulin-resistant PCOS patients with low BMI.

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[Primary lymphoma of breast: a clinicopathologic, immunophenotypic and prognostic study of 21 cases].

To investigate the clinicopathologic and immunophenotypic features of primary breast lymphoma (PBL) and to discuss the diagnosis of the tumor. Twenty-one cases of PBL with follow up data were clinically reviewed. The histologic diagnosis of the tumor was based on the updated WHO Classification of tumors of hematopoietic and lymphoid tissues (2008). Immunohistochemistry was performed by SP method and antibodies selected were as follows: CD20, CD3epsilon, CD10, Bcl-6, MUM-1, CD5, Bcl-2, CD23, CD10, cyclin D1, CD43 and Ki67. (1) All 21 patients were female and the median age of patients was 48 years. The right and the left breasts were involved in 11 (52.4%) and 10 patients (47.6%), respectively. According to Ann Arbor staging system, 20 cases were stage I-II (95.2%), and the remaining case was stage IV (4.8%). For the international prognostic index (IPI), 19 cases were score 0-1, and 2 cases were score 2-3. For ECOG score, 19 cases were 0, and the remaining 2 cases were 1. (2) Histologically, all 21 cases (100%) were DLBCL. Immunohistochemically, the frequency of antigen expression was as follows: CD20 (100%), MUM-1 (14/21, 66.7%), bcl-6 (5/21, 23.8%), CD10 (0), bcl-2 (13/21, 61.9%), CD5 (1/21, 4.8%); Ki-67 index: 10 cases (47.6%) were less than 59%, with the expression of seven cases (33.3%) being 60% - 89%, and more than 90% in the remaining four cases (19.1%). The median Ki-67 index was 60%. All the cases were considered non germinal center B-cell-like type of DLBCL. (3) Follow-up data was available in 64% of the cases. One, two and five-year survival rates were 11 cases, 7 cases and 3 cases, respectively. All the cases of PBL in the current study were DLBCL, non germinal center B-cell-like type, and a diagnosis of PBL can only be established after excluding breast involvement in systemic lymphoma.

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Assessment of gastric acid output by H2 breath test.

The standard method to measure gastric acid secretion is the aspiration of gastric juice. A noninvasive breath test after application of magnesium has been proposed. The aim of this study was to modify the method, to possibly improve the discriminatory value of the test in comparison with intubation tests. We measured the time course of the reaction of magnesium and gastric acid in vitro and determined the gastric hydrogen kinetics in humans by insufflation of hydrogen into the stomach and measuring its reappearance in the exhaled air. Thereafter, a comparison of the breath test and the intubation test was done in 10 healthy volunteers in different secretory states. After hydrogen insufflation 31.4% reappeared in 90 min (16.3% exhaled, rest belched). Discriminant analysis showed that the intubation test had a good discriminatory power. On the other hand, the breath test failed to distinguish between different secretory states (stimulation, inhibition, and intermediate). Whereas the intubation test discriminated between high and low acid secretion, the breath test did not. This test therefore seems, at least as performed here, unsuitable as a diagnostic test of gastric acid secretion.

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Peritonsillar abscess in children in the southern district of Israel.

Peritonsillar abscess is the most common deep neck infection and still provides a challenge to care givers in terms of diagnosis and treatment in the pediatric population. This study reviews our experience over the years 2004-2007 at the Soroka University Medical Center in the southern district of Israel in treating children with peritonsillar abscess. We compared our results with data regarding peritonsillar abscess in adults. We performed a retrospective chart review of 126 children diagnosed and proved to have a peritonsillar abscess. Data regarding: age, sex, ethnicity, number of patients per year, seasonality, prior history of tonsillar infection, prior antibiotic treatment, length of hospitalization, surgical treatment, bacterial results and in hospital antibiotic treatment was collected from the medical charts of the patients. The average age of children with peritonsillar abscess was 12.8 years. 92 patients (73%) were above 10 years of age. We did not find an increase in the number of children with peritonsillar abscess per year over the time period of the study. The number of patients with peritonsillar abscess was significantly higher in the autumn and spring, 79 (62.6%) patients did not have prior history of tonsillar infections and 64 (67.4%) children were treated with antibiotics prior to the diagnosis of an abscess. In 95 (75.4%) patients the drainage method was needle aspiration, in 30 (28.3%) patients incision and drainage was performed and only one patient underwent bilateral quinsy tonsillectomy (0.8%). The bacterial culture was negative in 37 (36.7%) patients. In 29 patients (45% of positive cultures) the causative organism was Streptococcus group A. Mixed culture was present in 10 (15.6%) patients, nine cultures (14%) were positive for anaerobes, alone or in combination with other pathogens. Eighty-one patients (64.2%) were treated with amoxicillin-clavulanate potassium, 24 (19%) received cefuroxime and 17 (13.5%) were treated with cefuroxime+ metronidazole. The average hospital stay was 3 days. Peritonsillar abscess, a potentially life threatening infection, is similar in presentation and bacteriology in the pediatric and the adult population. Based on our review we conclude that peritonsillar abscess in children can be effectively treated by the same methods used in the adult population.

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Risk of stroke in patients with high on-clopidogrel platelet reactivity to adenosine diphosphate after percutaneous coronary intervention.

Several prospective studies have shown that high on-clopidogrel platelet reactivity (HPR) in patients undergoing percutaneous coronary intervention (PCI) is a risk factor for ischemic events. All studies were insufficiently powered to detect differences in stroke between patients with HPR and those without. Therefore, we performed a systematic review and meta-analysis of available publications aimed at determining whether patients undergoing PCI with HPR are also at increased risk of stroke. We searched for prospective studies enrolling patients undergoing PCI and treated with aspirin and clopidogrel that reported on clinical relevance of HPR to adenosine diphosphate. Study end point was the rate of stroke. We also investigated whether there was an interaction on the relative risk of stroke between HPR, clinical presentation, duration of follow-up, or laboratory methods. Fourteen studies including 11,959 patients were deemed eligible. On pooled analysis, the risk of stroke was higher in patients with HPR compared with patients with no HPR (1.2% vs 0.7%, relative risk on fixed effect 1.84, 95% confidence interval 1.21 to 2.80). There was no heterogeneity among the studies (I(2) = 0%, p = 0.5). Clinical presentation (p = 0.39 for interaction), duration of follow-up (p = 0.87 for interaction), and laboratory method for detection of HPR (p = 0.99 for interaction) did not affect the relative increase in the risk of stroke in patients with HPR compared with patients with no HPR. In conclusion, in patients with coronary artery disease undergoing PCI, the presence of HPR to adenosine diphosphate is a risk factor for stroke.

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Thrombus and antiplatelet therapy in type 2 diabetes mellitus. A prospective study after non-ST elevation acute coronary syndrome and a randomised, blinded, placebo-controlled study in stable angina.

Type 2 diabetes mellitus (T2DM) is associated with higher rates of thrombotic complications in patients with coronary artery disease (CAD) despite optimal medical therapy. Thrombus area was measured in T2DM and non-diabetic patients receiving aspirin and clopidogrel 7-10 days after troponin positive Non ST-elevation acute coronary syndrome (NSTE-ACS). Secondly, we assessed response to clopidogrel in naive patients with T2DM and stable CAD in a randomised controlled trial. Thrombus area was measured by Badimon chamber and platelet reactivity by VerifyNow®. In T2DM patients presenting with NSTE-ACS, thrombus area was greater compared to non-diabetic patients (mean ± SD, 20,512 ± 12,567 [n=40] vs. 14,769 ± 8,531 [n=40] μm²/mm, p=0.02) Clopidogrel decreased thrombus area among stable CAD patients with T2DM (mean ± SD, Clopidogrel [n=45]: 13,978 ± 5,502 to 11,192 ± 3,764 μm²/mm vs. placebo [n=45]: 13,959 ± 7,038 to 14,201 ± 6,780 μm²/mm, p<0.001, delta values: clopidogrel vs. placebo, mean ± SD, 2,786 ± 4,561 vs. -249 ± 2,478, p<0.0005). Only 44% of patients with CAD and T2DM responded to clopidogrel as per VerifyNow® (cut-off PRUz value of ≥ 240). Importantly, no correlation was observed between thrombus area and VerifyNow® values (rho 0.08, p=0.49). Thrombus area values were similar among hypo-responders and good responders to clopidogrel (mean thrombus area ± SD: 12,186 ± 4,294 vs. 10,438 ± 3,401; p=0.17). Type 2 diabetes mellitus is associated with an increased blood thrombogenicity among NSTE-ACS patients on currently recommended medical therapy. Thrombus area was significantly reduced in all stable CAD patients independently of their response to clopidogrel therapy.

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Helicobacter pylori antibiotic susceptibility patterns in Bangladesh: Emerging levofloxacin resistance.

The most recent study to report Helicobacter pylori antibiotic resistance rates in Bangladesh was published 15 years ago and did not include levofloxacin. We therefore aimed to determine the current antibiotic susceptibility of H. pylori to amoxicillin, clarithromycin, metronidazole, tetracycline and levofloxacin in Bangladesh. This study included 133 consecutive patients who underwent endoscopy examination at Dhaka Medical College in November 2014. The serial two-fold agar dilution method was used to determine the minimum inhibitory concentrations of the five antibiotics. Among 56 cultured strains, H. pylori showed high rates of resistance to clarithromycin and metronidazole (39.3% and 94.6%, respectively). Moreover, levofloxacin showed an emerging antimicrobial resistance pattern (66.1%), which was higher in patients with gastritis than that in those with peptic ulcers (p = 0.02). The resistance rate of levofloxacin was significantly higher in patients living in Dhaka city compared to those living in the village (p = 0.049). However, amoxicillin and tetracycline resistance rates were very low. Resistance to both metronidazole and levofloxacin was most commonly observed. The rates of resistance to clarithromycin, metronidazole, and levofloxacin were high in Bangladesh, which suggests that triple therapy based on these drugs may not be useful as first-line therapies in Bangladesh. Alternative strategies such as furazolidone-based triple therapy, bismuth-based quadruple therapies, or sequential therapy may be more effective for patients in in Bangladesh.

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Single-dose efficacy of ofloxacin in uncomplicated gonorrhea.

Two multicenter trials compared single-dose oral therapy with 400 mg of ofloxacin or 3 g of amoxicillin plus 1 g of probenecid in the treatment of uncomplicated gonorrhea in 160 men and 102 women. Patients with a known diagnosis of Chlamydia trachomatis infection were excluded. All pretreatment isolates of Neisseria gonorrhoeae were susceptible to ofloxacin (minimal inhibitory concentration less than or equal to 2 micrograms/ml), whereas roughly 50 percent exhibited intermediate susceptibility to ampicillin (minimal inhibitory concentration, 0.125 to 2.0 micrograms/ml). Post-treatment culture results showed that ofloxacin had eradicated N. gonorrhoeae in 97.5 percent (41 men) of 42 men and all 28 women evaluated. Amoxicillin-probenecid achieved microbiologic cures in 92.7 percent (51 men) of 55 men and 92.6 percent (25 women) of 27 women evaluated. Clinical cure rates among initially symptomatic patients were 84.6 percent (33 men) of 39 men and 81.8 percent (nine women) of 11 women with ofloxacin and 83.0 percent (44 men) of 53 men and 66.7 percent (10 women) of 15 women with amoxicillin-probenecid. No drug-related adverse effects were noted in ofloxacin-treated patients. One patient each in the amoxicillin-probenecid group reported nausea, diarrhea, and vaginitis. These results demonstrate that single-dose ofloxacin is as effective as amoxicillin-probenecid in eradicating N. gonorrhoeae and relieving clinical signs and symptoms of gonococcal infections in both men and women.

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Lung function and asthma control with beclomethasone and formoterol in a single inhaler.

Lung deposition is crucial for asthma treatment. However, there is no study comparing the potential role of lung co-deposition of combination therapy (inhaled corticosteroid and long-acting beta2 agonist) in the same inhaler. In moderate to severe asthmatics, an extra-fine hydrofluoroalkane combination of beclomethasone dipropionate and formoterol given via a single pressurised metered-dose inhaler (pMDI) was compared with beclomethasone dipropionate chlorofluorocarbon (CFC) pMDI and formoterol dry powder inhaler (DPI) given via separate inhalers. In a double-blind, double-dummy, 24-week randomised clinical trial, 645 patients with moderate to severe asthma uncontrolled by regular treatment with inhaled corticosteroids received regular treatment with extra-fine fixed combination beclomethasone dipropionate 200 microg/formoterol 12 microg bid, or beclomethasone dipropionate (500 microg bid) via CFC pMDI and formoterol (12 microg bid) via DPI, or beclomethasone dipropionate (500 microg bid) via CFC pMDI. The primary outcome was morning peak expiratory flow (PEF). Secondary outcomes included lung function measured at clinic, asthma symptoms and control, exacerbations. Beclomethasone dipropionate/formoterol combination via single inhaler or via separate inhalers improved morning PEF. However, the combination via single inhaler was more effective than given via separate inhalers for asthma control. Both combination treatments were superior to beclomethasone dipropionate alone in improving lung function and asthma control. All treatments were well tolerated. In patients with moderate to severe asthma, beclomethasone dipropionate/formoterol in a single inhaler was as effective as beclomethasone dipropionate plus formoterol and superior to beclomethasone dipropionate alone in improving lung function. For the first time with a single inhaler, beclomethasone dipropionate/formoterol was significantly superior to separate components for asthma control.

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Proof of concept for the clinical effects of oral rilzabrutinib, the first Bruton tyrosine kinase inhibitor for pemphigus vulgaris: the phase II BELIEVE study.

Bruton tyrosine kinase (BTK) inhibition targets B-cell and other non-T-cell immune cells implicated in the pathophysiology of pemphigus, an autoimmune disease driven by anti-desmoglein autoantibodies. Rilzabrutinib is a new reversible, covalent BTK inhibitor demonstrating preclinical efficacy as monotherapy in canine pemphigus foliaceus. To evaluate the efficacy and safety of oral rilzabrutinib in patients with pemphigus vulgaris in a multicentre, proof-of-concept, phase II trial. Patients with Pemphigus Disease Area Index severity scores 8-45 received 12 weeks of oral rilzabrutinib 400-600 mg twice daily and 12 weeks of follow-up. Patients initially received between 0 and ≤ 0·5 mg kg^-1 prednisone-equivalent corticosteroid (CS; i.e. 'low dose'), tapered after control of disease activity (CDA; no new lesions, existing lesions healing). The primary endpoints were CDA within 4 weeks on zero-to-low-dose CS and safety. In total, 27 patients with pemphigus vulgaris were included: nine newly diagnosed (33%) and 18 relapsing (67%); 11 had moderate disease (41%) and 16 moderate to severe (59%). The primary endpoint, CDA, was achieved in 14 patients (52%, 95% confidence interval 32-71): 11 using low-dose CS and three using no CS. Over 12 weeks of treatment, mean CS doses reduced from 20·0 to 11·8 mg per day for newly diagnosed patients and from 10·3 to 7·8 mg per day for relapsing patients. Six patients (22%) achieved complete response by week 24, including four (15%) by week 12. Treatment-related adverse events were mostly mild (grade 1 or 2); one patient experienced grade 3 cellulitis. Rilzabrutinib alone, or with much lower CS doses than usual, was safe, with rapid clinical activity in pemphigus vulgaris. These data suggest that BTK inhibition may be a promising treatment strategy and support further investigation of rilzabrutinib for the treatment of pemphigus.

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[Clonazepam in the treatment of protracted depression: a hundred-case report].

Clonazepam, which presently is recommended for the treatment of seizure disorders, has been reported to be useful as an adjunctive treatment for depression. The purpose of this paper was to examine the suitable adjunctive dose and the characteristics of clonazepam for the treatment of protracted depression. A hundred protracted depressive patients treated with clonazepam were studies by the retrospective method. A daily dose of 3.0 mg clonazepam as augmentation expressed high effectiveness (78.4%) on protracted depression. Most of the improved patients showed a rapid onset of action within two weeks. Gender, age, phase number, family history of psychosis, and clinical symptoms did not change the effectiveness of clonazepam treatment. A daily dose of at least 3.0 mg clonazepam as augmentation of ongoing antidepressant treatment should be considered for protracted depressive patients with suboptimal improvement. Unipolar depression was significantly more effective than bipolar depression on clonazepam treatment. The clear-cut difference in response to unipolar and bipolar depression suggests that the underlying abnormality in unipolar depression is not the same as that in bipolar depression. A continuance of clonazepam after improvement disturbed the recurrence of depression, and it seems that clonazepam augmentation has a preventive effect.

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Clinical Presentation, Predictors, and Outcomes Among Mineralocorticoid Receptor Antagonist (MRA)-Eligible Acute Heart Failure Patients in the Heart Function Assessment Registry Trial in Saudi Arabia (HEARTS).

Mineralocorticoid receptor antagonist (MRA) therapy is indicated after myocardial infarction in patients with acute heart failure (AHF) with an ejection fraction ≤40% and lacking contraindications. We analyzed clinical presentations, predictors, and outcomes of MRA-eligible patients within a prospective registry of patients with AHF from 18 hospitals in Saudi Arabia, from 2009 to 2010. For this subgroup, mortality rates were followed until 2013, and the clinical characteristics, management, predictors, and outcomes were compared between MRA-treated and non-MRA-treated patients. Of 2609 patients with AHF, 387 (14.8%) were MRA eligible, of which 146 (37.7%) were prescribed MRAs. Compared with non-MRA-treated patients, those prescribed MRAs more commonly exhibited non-ST-segment elevation myocardial infarction, acute on chronic heart failure, past history of ischemic heart disease, and severe left ventricular systolic dysfunction; were more commonly administered oral furosemide and digoxin; and had higher in-hospital recurrent congestive HF rates. Mortality did not significantly differ ( P > .05) between groups. In Saudi Arabia, 37.7% of eligible patients received MRA treatment, which is higher than that in developed countries. The lack of long-term survival benefit raises concerns about systematic problems, for example, proper follow-up and management after hospital discharge, warranting further investigation.

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Pharmacokinetics of tramadol and its three main metabolites in healthy male and female volunteers.

By using a high-performance liquid chromatography method, the pharmacokinetics of the tramadol (T) and its three main metabolites, O-desmethyltramadol (M1), N-desmethyltramadol (M2) and O,N-didesmethyltramadol (M5) was studied in healthy male and female Iranian volunteers after oral administration of two 50 mg tramadol hydrochloride tablets. The related pharmacokinetic parameters such as C(max), T(max), AUC((0-t)), AUC((0-infinity)), T(1/2) and Cl/F were calculated and compared between the two genders. No significant differences were found in the systemic exposure and pharmacokinetic of tramadol, M1 and M2 while there were significant differences in AUCs of M5 in the two genders. It was concluded that to get a more accurate result, the gender dependency of T and its metabolites might be studied in specific phenotypes.

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Use of 99Tcm radionuclides to show nephrotoxicity of cyclosporin A in transplanted kidneys.

In 60 patients, 99Tcm pertechnetate or 99Tcm methylene diphosphonate was injected through an arm vein within 36 h after renal transplantation and repeated 24 or 48 h later. Thirty-one were treated with azathioprine and prednisone, 27 of the grafts had a well-defined peak on the histograms similar to that from the iliac artery histograms at both examinations. In contrast, of the 29 patients treated with cyclosporin A, only 5 of the grafts had a well-defined peak at both examinations. The difference is highly significant. Treatment with cyclosporin A causes a decrease in renal blood flow in the days immediately after transplantation.

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Methylphenidate: rate-dependent drug effects in hyperactive boys.

The purpose of this study was to test whether the effects of methylphenidate on rates of operant responding in hyperactive boys differed depending on the predrug baseline rates of responding. On the basis of the rate dependency hypothesis, dose-related decreases from high baseline rates and increases from low baseline rates would be predicted. A multiple FR-DRL (fixed ratio-differential reinforcement of low Rates) schedule was used to generate high and low rates of responding on a simple operant task, using nickels as reinforcers. Three dosage levels were used: placebo, 0.3 mg/kg, and 1.0 mg/kg of methylphenidate. Both experimenter and subject were blind to dosage level. Surprisingly, DRL response rates were not significantly affected by the drug, while FR rates increased linearly with increasing dose. Thus, the predicted between-schedule differences were not found. However, within the FR schedule, changes from baseline to postdrug rates within each active drug condition were consistent with the rate dependency hypothesis; i.e., subjects with lower baselines increased their response rates, while subjects with higher baselines decreased or did not change their rates. The opposite effect occurred following placebo.

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Effectiveness and safety of oral anticoagulants in older adults with non-valvular atrial fibrillation and heart failure.

Direct oral anticoagulants (DOACs) are at least as efficacious and safe as warfarin among non-valvular atrial fibrillation (NVAF) patients; limited evidence is available regarding NVAF patients with heart failure (HF). US Medicare enrollees with NVAF and HF initiating DOACs (apixaban, rivaroxaban, dabigatran) or warfarin were selected. Propensity score matching and Cox models were used to estimate the risk of stroke/systemic embolism (SE), major bleeding (MB), and major adverse cardiac events (MACE) comparing DOACs versus warfarin and DOACs versus DOACs. We identified 10,570 apixaban-warfarin, 4,297 dabigatran-warfarin, 15,712 rivaroxaban-warfarin, 4,263 apixaban-dabigatran, 10,477 apixaban-rivaroxaban, and 4,297 dabigatran-rivaroxaban matched pairs. Compared to warfarin, apixaban had lower rates of stroke/SE (hazard ratio = 0.64, 95% confidence interval = 0.48-0.85), MB (hazard ratio = 0.66, 0.58-0.76), and MACE (hazard ratio = 0.73,0.67-0.79); dabigatran and rivaroxaban had lower rates of MACE (hazard ratio = 0.87,0.77-0.99; hazard ratio = 0.84, 0.79-0.89, respectively). Rivaroxaban had a lower stroke/SE rate (hazard ratio = 0.65, 0.52-0.81) and higher MB rate (hazard ratio = 1.18, 1.08-1.30) versus warfarin. Compared to dabigatran and rivaroxaban, apixaban had lower MB (hazard ratio = 0.71, 0.57-0.89; hazard ratio = 0.55, 0.49-0.63) and MACE rates (hazard ratio = 0.80, 0.69-0.93; hazard ratio = 0.86, 0.79-0.94), respectively. All DOACs had lower MACE rates versus warfarin; differences were observed in stroke/SE and MB. Our findings provide insights about OAC therapy among NVAF patients with HF.

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Association of statin use with improved local control in patients treated with selective bladder preservation for muscle-invasive bladder cancer.

To assess whether statin use improves local control (LC) in patients undergoing organ-preserving trimodality therapy for muscle-invasive bladder cancer. We retrospectively analyzed the data from 286 patients with muscle-invasive, transitional cell carcinoma of the bladder treated with maximal transurethral resection of the bladder tumor followed by chemoradiotherapy from 1986 to 2003 at the Massachusetts General Hospital. Patients with a complete response after induction chemoradiotherapy received consolidation chemoradiotherapy and those with an incomplete response underwent cystectomy. Of the 286 patients, 35 (12%) were known to be taking a statin during chemoradiotherapy. LC was defined as freedom from the development of muscle-invasive bladder cancer or superficial bladder cancer necessitating cystectomy. The median follow-up time was 2.7 years for all patients and 3.1 years for survivors. The overall 5-year LC rate was 55%. On univariate analysis, tumor stage, completeness of transurethral resection of the bladder tumor, hydronephrosis, chemotherapy type, treatment era, and statin use were significantly associated with LC. The 5-year LC rate for patients taking a statin was 73% versus 52% for patients not taking a statin (P = 0.04). On multivariate analysis incorporating covariates that were statistically significant (P < 0.05) on univariate analysis, only chemotherapy with cisplatin (P = 0.02) and the absence of hydronephrosis (P = 0.01) remained significantly associated with LC. Statin use was associated with an improvement in LC on univariate analysis but was not found to be independently associated with LC after controlling for known prognostic factors. The potential beneficial interaction between statin use and chemoradiotherapy in bladder cancer warrants further investigation in a prospective study.

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Efficacy and cost comparisons of bronchodilatator administration between metered dose inhalers with disposable spacers and nebulizers for acute asthma treatment.

Despite demonstration of equivalent efficacy of beta agonist delivery using a metered dose inhaler (MDI) with spacer vs. nebulizer in asthma patients, use of a nebulizer remains standard practice. We hypothesize that beta agonist delivery with a MDI/disposable spacer combination is an effective and low-cost alternative to nebulizer delivery for acute asthma in an inner-city population. This study was a prospective, randomized, double-blinded, placebo-controlled trial with 60 acute asthma adult patients in two inner-city emergency departments. Subjects (n = 60) received albuterol with either a MDI/spacer combination or nebulizer. The spacer group (n = 29) received albuterol by MDI/spacer followed by placebo nebulization. The nebulizer group (n = 29) received placebo by MDI/spacer followed by albuterol nebulization. Peak flows, symptom scores, and need for rescue bronchodilatator were monitored. Median values were compared with the Kolmogorov-Smirnov test. Patients in the two randomized groups had similar baseline characteristics. The severity of asthma exacerbation, median peak flows, and symptom scores were not significantly different between the two groups. The median (interquartile range) improvement in peak flow was 120 (75-180) L/min vs. 120 (80-155) L/min in the spacer and nebulizer groups, respectively (p = 0.56). The median improvement in the symptom score was 7 (5-9) vs. 7 (4-9) in the spacer and nebulizer groups, respectively (p = 0.78). The median cost of treatment per patient was $10.11 ($10.03-$10.28) vs. $18.26 ($9.88-$22.45) in the spacer and nebulizer groups, respectively (p < 0.001). There is no evidence of superiority of nebulizer to MDI/spacer beta agonist delivery for emergency management of acute asthma in the inner-city adult population. MDI/spacer may be a more economical alternative to nebulizer delivery.

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The effect of losartan and amlodipine on left ventricular diastolic function and atherosclerosis in Japanese patients with mild-to-moderate hypertension (J-ELAN) study.

This study was a prospective, randomized, open, blinded endpoint study to assess the effects of angiotensin II type 1 receptor blocker, losartan, compared with calcium channel blocker, amlodipine, on left ventricular (LV) diastolic function and atherosclerosis of the carotid artery in Japanese patients with mild-to-moderate hypertension, LV hypertrophy, diastolic dysfunction and preserved systolic function. Fifty-seven patients were randomly assigned to losartan- or amlodipine-based treatment groups and were followed up for 18 months. Blood pressure was similarly reduced by both regimens. Losartan shortened the transmitral E-wave deceleration time, and amlodipine reduced LV mass index; however, there was no significant difference in the percent changes of these indices between the two groups. Mean carotid intima-media thickness (mean IMT) as well as plaque score significantly increased in the amlodipine-based regimen (pre: 1.05±0.26 mm, follow-up: 1.23±0.33 mm, P=0.0015), but not in the losartan-based regimen (pre: 1.08±0.35 mm, follow-up: 1.16±0.52 mm, P=non-significant). The percent increase in mean IMT in the amlodipine-based regimen tended to be large compared with the losartan-based regimen (amlodipine: 19.8±23.7%, losartan: 6.9±23.3%, P=0.06). Under similar reduction of blood pressure, losartan is likely effective in protecting the progression of atherosclerosis of the carotid artery compared with amlodipine. Losartan may improve LV diastolic function, and amlodipine may attenuate LV hypertrophy; however, this study cannot make consecutive remarks about the superiority of either treatment regimen in the effects on cardiac function and geometry. This study has been registered at http://www.umin.ac.jp/ctr/listj/ (identifier C000000319).

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Obstetric duplex sonography in patients with lupus anticoagulant syndrome.

The lupus anticoagulant (LAC) syndrome has recently been described as a potential cause of many cases of preeclampsia. This syndrome is associated with a maternal history of repeated first trimester abortions and second and third trimester demise in utero. Umbilical arterial duplex Doppler systolic/diastolic (S/D) ratios and uterine artery S/D ratios for 28 patients whose pregnancies were complicated by lupus anticoagulant syndrome are presented. Five of the six patients who subsequently delivered fetuses small for gestational age (SGA) demonstrated abnormal umbilical arterial S/D ratios, whereas only two of these patients demonstrated abnormally elevated uterine S/D ratios. Twenty three of 28 patients were treated with aspirin and prednisone throughout gestation; no cases of fetal demise in utero were noted.

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[Treatment outcome analysis of CTOP or CHOP regimen in newly diagnosed aggressive non-Hodgkin's lymphoma patients-results of a prospective, open, randomized, multicenter clinical trial].

To compare the efficacy and toxicity of CTOP and CHOP regimen for newly diagnosed aggressive non-Hodgkin's lymphoma (NHL) patients. From Oct 2006 to Jun 2009, 196 patients enrolled into this clinical trial from 72 centers in China were randomized into CTOP or CHOP group. Of 154 patients evaluated, 105 assigned in CTOP group and 49 in CHOP. Complete remission (CR) rate was 73.3%, and response rate (RR) was 87.6% in CTOP group and CR rate 71.4%, RR 86.2% in CHOP group, respectively (both P > 0.05). For B cell lymphomas, there was no difference in outcome between the two groups, but for T cell lymphomas, CR was 71.1% in CHOP, being significantly higher than that of 58.8% in CHOP group. There was no difference in hematological toxicity, GI reaction, liver and kidney function abnormality, but the occurrence of grade 3-4 alopecia in CTOP group (12.4%) was significantly lower than that in CHOP group (40.8%). The progress-free survival and overall survival (PFS and OS) at 1-, 2-, 3-year in CTOP group were 79%, 64.8%, 51.4% and 82.9%, 70.5%, 58.1%respectively; while in CTOP group were 77.6%, 61.2%, 49% and 81.6%, 67.3%, 55.1% respectively. CTOP regimen has similar effectiveness to CHOP regimen in newly diagnosed aggressive NHL, but with less side effects, and better efficacy for T cell lymphomas.

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'Scheduled' dosing of lornoxicam provides analgesia superior to that provided by 'on request' dosing following craniotomy.

The aim of this study was to compare the efficacy of 'scheduled' analgesia with analgesia 'on request in patients after craniotomy. We performed a prospective randomized study comparing 'scheduled' analgesia with analgesia 'on request' on 126 patients aged 16-70 years undergoing craniotomy for a variety of reasons. Patients were randomized to one of two groups; group 1 (68 patients) received lornoxicam 'on request', and group 2 (58 patients) received 8 mg of lornoxicam preoperatively, immediately after intubation, then 8 mg again 6-8 h after the first injection and 8 mg repeated every 8 h for 48 h postoperatively. Subgroup analysis was performed for patients with supratentorial and infratentorial craniotomy. We measured pain scores (visual analogue scale), mean blood pressure and heart rate at 6, 18, 30, 42 and 54 h after surgery and compared differences in these parameters between groups and amongst subgroups. Group 1 visual analogue pain scale scores were significantly higher than those in group 2 (P < 0.05). Group 1 patients with infratentorial craniotomy showed higher pain scores than supratentorial craniotomy patients (P < 0.05). No significant differences were observed in mean blood pressure between groups and subgroups (P > 0.05). We found no correlation between visual analogue scale scores, mean blood pressure and heart rate (P > 0.05). 'Scheduled' analgesia with lornoxicam was more effective for treating post-craniotomy pain than 'on request' analgesia with lornoxicam.

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CARL: a LabVIEW 3 computer program for conducting exposure therapy for the treatment of dental injection fear.

This paper describes CARL (Computer Assisted Relaxation Learning), a computerized, exposure-based therapy program for the treatment of dental injection fear. The CARL program operates primarily in two different modes; in vitro, which presents a video-taped exposure hierarchy, and in vivo, which presents scripts for a dentist or hygienist to use while working with a subject. Two additional modes are used to train subjects to use the program and to administer behavioral assessment tests. The program contains five different modules, which function to register a subject, train subjects to use physical and cognitive relaxation techniques, deliver an exposure hierarchy, question subjects about the helpfulness of each of the therapy components, and test for memory effects of anxiolytic medication. Nine subjects have completed the CARL therapy program and 1-yr follow-up as participants in a placebo-controlled clinical trial examining the effects of alprazolam on exposure therapy for dental injection phobia. All nine subjects were able to receive two dental injections, and all reduced their general fear of dental injections. Initial results therefore indicate that the CARL program successfully reduces dental injection fear.

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Effect of cholesterol-lowering therapy on coronary endothelial vasomotor function in patients with coronary artery disease.

Improved endothelial function may contribute to the beneficial effects of cholesterol-lowering therapy. In this randomized, double-blind study, we compared the effect of 6 months of simvastatin (40 mg/d) treatment with that of placebo on coronary endothelial vasomotor function in 60 patients with coronary artery disease. Simvastatin lowered LDL-cholesterol by 40+/-12% from 130+/-28 mg/dL (P<0.001). Peak intracoronary acetylcholine infusion produced epicardial coronary constriction at baseline in both the simvastatin (-17+/-13%) and placebo (-24+/-16%) groups. After treatment, acetylcholine produced less constriction in both groups (-12+/-19% and -15+/-14%, respectively, P=0.97). The increase in coronary blood flow during infusion of the peak dose of substance P was blunted at baseline in both the simvastatin (42+/-50%) and placebo (55+/-71%) groups, reflecting impaired endothelium-dependent dilation of coronary microvessels. After treatment, the flow increase was 82+/-81% in the simvastatin group and 63+/-53% in the placebo group (P=0.16). Six months of cholesterol-lowering therapy has no significant effect on coronary endothelial vasomotor function in the study population of patients with coronary artery disease and mildly elevated cholesterol levels. These findings suggest that the effects of cholesterol lowering on endothelial function are more complex than previously thought.

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[Helicobacter pylori eradication heals the duodenal ulcer. Randomized, simple, and controlled study with omeprazole].

60 patients with Helicobacter pylori (Hp) infection and duodenal ulcer (DU) were randomized to received either: I) Two weeks of bismuth subcitrate, metronidazole and amoxicillin (TG) or II) Omeprazole for four weeks (OG). Endoscopy and antral biopsies were done at entry and four weeks after treatment, control endoscopy was performed 2-4-8 and 12 weeks after inclusion in the trial. Healing was similar in both groups at two four weeks. At twelve weeks DU recurred in OG 65% vs 13.36% in TG and Hp infection was present. Our results showed that Hp eradication healed DU in a similar rate than Omeprazole providing further evidence of a causal link between Hp infection and duodenal ulcer.

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Clinical, Cellular, and Molecular Evidence of the Additive Antitumor Effects of Biguanides and Statins in Prostate Cancer.

Prostate cancer (PCa) is one of the leading causes of cancer-related death among the male population worldwide. Unfortunately, current medical treatments fail to prevent PCa progression in a high percentage of cases; therefore, new therapeutic tools to tackle PCa are urgently needed. Biguanides and statins have emerged as antitumor agents for several endocrine-related cancers. To evaluate: (1) the putative in vivo association between metformin and/or statins treatment and key tumor and clinical parameters and (2) the direct effects of different biguanides (metformin/buformin/phenformin), statins (atorvastatin/simvastatin/lovastatin), and their combination, on key functional endpoints and associated signalling mechanisms. An exploratory/observational retrospective cohort of patients with PCa (n = 75) was analyzed. Moreover, normal and tumor prostate cells (normal [RWPE-cells/primary prostate cell cultures]; tumor [LNCaP/22RV1/PC3/DU145 cell lines]) were used to measure proliferation/migration/tumorsphere-formation/signalling pathways. The combination of metformin+statins in vivo was associated to lower Gleason score and longer biochemical recurrence-free survival. Moreover, biguanides and statins exerted strong antitumor actions (ie, inhibition of proliferation/migration/tumorsphere formation) on PCa cells, and that their combination further decreased; in addition, these functional parameters compared with the individual treatments. These actions were mediated through modulation of key oncogenic and metabolic signalling pathways (ie, AR/mTOR/AMPK/AKT/ERK) and molecular mediators (MKI67/cMYC/androgen receptor/cell-cycle inhibitors). Biguanides and statins significantly reduced tumor aggressiveness in PCa, with this effect being more potent (in vitro and in vivo) when both compounds are combined. Therefore, given the demonstrated clinical safety of biguanides and statins, our results suggest a potential therapeutic role of these compounds, especially their combination, for the treatment of PCa.

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DNA methylation inhibition in myeloma: Experience from a phase 1b study of low-dose continuous azacitidine in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma.

The DNA methyltransferase inhibitor azacytidine (aza) may reactivate pathways associated with plasma cell differentiation, cell cycle control, apoptosis, and immune recognition and thereby restore sensitivity to lenalidomide (len) and dexamethasone (dex) in relapsed and/or refractory multiple myeloma (RRMM). We aimed to develop an aza regimen that reaches epigenetically active levels 8 times in 28 days with less bone marrow toxicity than the myeloid malignancy standard of 7 consecutive doses to enable safe combination with len. Aza was escalated from 30 mg/m² once a week up to a predefined maximum of 50 mg/m² twice a week in combination with GFR-adjusted len (≥ 60 mL/min: 25 mg, 3059 mL/min: 10 mg) day 1 to 21 every 28 days and dex 40 mg once a week followed by a limited expansion study to a total N of 23 at the highest tolerated dose. Fifty-one patients (pts) with RRMM were screened, 42 were treated and 41 were evaluable for response based on at least 1 response assessment or progression after treatment start. The median number of prior lines of therapy was 5 (1-11) and 81% (34) were refractory to len and/or pomalidomide (pom). Two DLTs occurred in different cohorts, 1 neutropenic fever in 1/6 pts on the aza 40 mg/m² twice a week GFR ≥ 60 mL/min cohort and 1 GGT elevation in 1/6 pts on the aza 50 mg/m² GFR 30-59 mL/min cohort. An MTD was not reached and aza 50 mg/m² SC twice a week was chosen for the expansion study. At least possibly related Grade 3/4 AEs occurred in 28 pts (67%) with the following in > 1 pt: neutropenia (N = 16, 38%), anemia (N = 6, 14%), lymphopenia (N = 5, 12%), thrombocytopenia (N = 4, 10%), leukopenia (N = 4, 10%), febrile neutropenia (N = 4, 10%), fatigue (N = 3, 7%), fever (N = 2, 5%), and infection (N = 2, 5%). At a median follow up time for alive pts of 60.2 months (range: 36.1-82.5 months), the overall response rate (≥ partial response) and clinical benefit response rate (≥ minor response) was 22 and 32%, respectively, with 4 very good partial responses (10%), 5 partial responses (12%), and 4 minor responses (10%). The median PFS was 3.1 months (95% confidence interval [CI]: 2.1-5.1 months), median TTP 2.7 months (95% CI: 2.1-7.5 months), and median OS 18.6 months (95% CI: 12.9-33.0 months). Achieving at least minor response and reaching TTP > 6 months was associated with approximately 35% lower median plasma levels of the enzyme that inactivates aza, plasma cytidine deaminase (CDA, P< .0001). Two of the len refractory pts achieved longer disease control than with any prior regimen and 1 responded immediately after progression on len, bortezomib, and prednisone. Analyses of the methylation state of over 480,000 CpG sites in purified myeloma cells at screening were possible in 11 pts and on day 28 in 8 of them. As in other studies, the majority of differentially methylated CpGs compared to normal plasma cells were hypomethylated in myeloma. Treatment decreased the number of CpGs that were differentially methylated in normal plasma cells by > 0.5% in 6 and by > 5% in 3 of the 8 pts, most pronounced in 2 pts with clinically convincing aza contribution who achieved a reduction in overall differentially methylated CpGs by 23 and 68%, respectively, associated with increased expression of immunoglobulin genes. The study demonstrated tolerability of twice a week SC aza at 50 mg/m² with len and dex in RRMM and suggested aza may help overcome the len/pom refractory state, possibly by activating differentiation pathways. Relatively low response rates and association of clinical benefit with low plasma levels of the aza inactivating enzyme CDA suggest the aza regimen will need to be optimized further and pt selection may be required to maximize benefit.

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Does thromboelastography predict bleeding in patients treated with clopidogrel or ticagrelor in off-pump coronary artery bypass grafting?

We sought to investigate the predictive value of platelet function assessment for bleeding in clopidogrel- or ticagrelor-treated patients undergoing off-pump coronary artery bypass grafting (OPCABG). This prospective study included patients treated with acetylsalicylic acid and clopidogrel or acetylsalicylic acid and ticagrelor and scheduled for OPCABG. The percentage of platelet aggregation was evaluated by thromboelastography. Postoperative blood loss was measured as the chest tube drainage (CTD) and excessive blood loss was settled as CTD with more than 600 mL at first postoperative 12 h. Major bleeding complications were defined by Bleeding Academic Research Consortium (BARC) type 4-CABG related bleeding or class 3 or class 4 bleeding in universal definition of perioperative bleeding (UDPB) in adult cardiac surgery. A total of 434 consecutive patients were included. There was a negative correlation (r = -0.133, P = 0.0056) between ADP-induced platelet aggregation and CTD at 12 h. The platelet aggregation exhibited a moderate performance (AUC = 0.616) for predicting excessive postoperative blood loss. Multivariable analysis showed that ADP-induced platelet aggregation <33.45% (OR = 2.976, 95% CI: 1.325-6.711, P = 0.008) was independently associated with excessive postoperative blood loss. However, the percentage of ADP-induced platelet aggregation predicted neither UDPB-defined nor BARC-defined major bleeding. Instead, P2Y₁₂ receptor antagonist discontinuation time was independently related to the risk of major bleeding complication. ADP-induced platelet aggregation detected by thromboelastography was negatively related to postoperative blood loss and platelet aggregation <33.45% was associated with excessive postoperative blood loss. However, platelet function assessment by thromboelastography failed to predict major bleeding complications.

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Prospective Monitoring of Donor-specific Anti-HLA Antibodies After Intestine/Multivisceral Transplantation: Significance of De Novo Antibodies.

Presence of circulating donor-specific antibodies (DSA) may be associated with worse clinical outcomes after intestine/multivisceral transplantation. In 79 intestine/multivisceral recipients, sera were prospectively screened for DSA by Luminex Single antigen test at 1, 3, 6, 9, 12, 18, 24, and 36 months after transplantation. Standard immunosuppression included thymoglobulin-rituximab induction and tacrolimus-prednisone maintenance. C4d staining was performed retrospectively on biopsies in patients that developed acute rejection (AR). Twenty-two (28%) patients developed de novo DSA at a median posttransplant period of 3 (1-36) months. De novo DSA were observed in 10 of 40 liver-including and 12 of 39 liver-excluding transplants (P = 0.57). Occurrence of AR was slightly higher in patients with de novo DSA (45% vs 33%, respectively; P = 0.41). Similarly, chronic rejection (14% vs 5%; P = 0.21) and graft loss due to AR (18% vs 7%; P = 0.14) were numerically higher in patients with de novo DSA. Only 35% patients experiencing AR had circulating de novo DSA at the time of AR. Antibody-mediated rejection was diagnosed in 6 patients based on C4d staining, of these 2 patients had circulating de novo DSA at the time of biopsy. De novo DSA formation, particularly early in the posttransplant course may be associated with trends toward worse outcomes. However, its significance in the pathophysiology of AR remains uncertain. Studies focusing mechanisms of DSA-related graft injury and intragraft DSA detection might provide further insight into this issue.

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A case of atrial fibrillation induced by inhaled fluticasone propionate.

Atrial fibrillation (AF) is the most common rhythm disorder observed in clinical practice. Several case reports and case-control studies have associated this condition with the use of systemic corticosteroids. However, to our knowledge, no case of AF induced by inhaled corticosteroids has been reported in the literature. We describe here the case of a 15-year-old boy who reported a paroxysmal AF with fast ventricular response after the administration of fluticasone propionate, which resolved after discontinuation of the drug. Use of the Naranjo adverse-drug-reaction probability scale indicated a possible relationship between the patient's development of AF and fluticasone propionate therapy. More studies are needed to confirm the association between this arrhythmia and the use of high doses of inhaled corticosteroids. Data from this report already suggest that clinicians should be aware of the possibility of adverse cardiovascular reactions when corticosteroids are prescribed also as inhaled preparations.

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Effects of non-steroidal anti-inflammatory drugs on hypertension control using angiotensin converting enzyme inhibitors and thiazide diuretics.

To determine the impact of three non-steroidal anti-inflammatory drugs on the efficacy of two anti-hypertensive drugs. Fifteen women with arthritis and hypertension who were receiving lisinopril and HCT, and administered sequentially in random order ibuprofen, sulindac, and diclofenac for one month each, with an intervening two-week washout period between each treatment period. During the washout period, subjects received paracetamol. Hypertension Clinic, Medical Centre, Harare, Zimbabwe. Fifteen female hypertensive women with documented arthritis. Blood pressure at the end of two weeks of paracetamol was compared with blood pressure after one month of treatment with each of the NSAID. Mean blood pressure was unchanged before and after all NSAIDs: 108 +/- 7 versus 107 +/- 9 for diclofenac, 108 +/- 9 versus 108 +/- 9 for sulindac, and 108 +/- 8 versus 107 +/- 9 for ibuprofen. The 24 hour urinary sodium excretion was not significantly different. The three NSAIDs investigated did not neutralise the antihypertensive effect of the combination of lisinopril and HCT, and hence the blood pressure lowering action of the combination may not be prostaglandin dependent.

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Detecting treatment-covariate interactions using permutation methods.

The primary objective of a Randomized Clinical Trial usually is to investigate whether one treatment is better than its alternatives on average. However, treatment effects may vary across different patient subpopulations. In contrast to demonstrating one treatment is superior to another on the average sense, one is often more concerned with the question that, for a particular patient, or a group of patients with similar characteristics, which treatment strategy is most appropriate to achieve a desired outcome. Various interaction tests have been proposed to detect treatment effect heterogeneity; however, they typically examine covariates one at a time, do not offer an integrated approach that incorporates all available information, and can greatly increase the chance of a false positive finding when the number of covariates is large. We propose a new permutation test for the null hypothesis of no interaction effects for any covariate. The proposed test allows us to consider the interaction effects of many covariates simultaneously without having to group subjects into subsets based on pre-specified criteria and applies generally to randomized clinical trials of multiple treatments. The test provides an attractive alternative to the standard likelihood ratio test, especially when the number of covariates is large. We illustrate the proposed methods using a dataset from the Treatment of Adolescents with Depression Study.

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Increased risk of atherothrombotic events associated with cytochrome P450 3A5 polymorphism in patients taking clopidogrel.

Clopidogrel is a prodrug requiring metabolism by cytochrome P450 3A (CYP3A) isoenzymes, including CYP3A5, in order to be active. It is controversial whether clopidogrel interacts with CYP3A inhibitors. We investigated the influence of CYP3A5 polymorphism on the drug interaction of clopidogrel. In phase 1 of the study, we administered clopidogrel to 16 healthy volunteers who had the CYP3A5 non-expressor genotype (*3 allele) and 16 who had the CYP3A5 expressor genotype (*1 allele) with and without pretreatment with itraconazole, a potent CYP3A inhibitor. A platelet aggregation test was performed at baseline, 4 hours, 24 hours and 6 days after clopidogrel administration. In phase 2, we compared clinical outcomes of 348 patients treated with clopidogrel after successful coronary angioplasty with bare-metal stent implantation according to their CYP3A5 genotype; the primary end point was a composite of atherothrombotic events (cardiovascular death, myocardial infarction and non-hemorrhagic stroke) within 1 and 6 months after stent implantation. In phase 1, the change in platelet aggregation after clopidogrel administration and pretreatment with itraconazole was greater among the subjects with the CYP3A5 expressor genotype than among those with the non-expressor genotype: 24.9% (standard deviation [SD] 13.9%) v. 6.2% (SD 13.5%) at 4 hours (p < 0.001); 27.7% (SD 16.5%) v. 2.5% (SD 8.3%) at 24 hours (p < 0.001); and 33.5% (SD 18.6%) v. 17.8% (SD 13.8%) at day 7 (p < 0.01). In phase 2, atherothrombotic events occurred more frequently within 6 months after stent implantation among the patients with the non-expressor genotype than among those with the expressor genotype (14/193 v. 3/155; p = 0.023). Multivariable analysis showed that the CYP3A5 polymorphism was a predictor of atherothrombotic events in clopidogrel users. People with the CYP3A5 non-expressor genotype are vulnerable to drug interactions between clopidogrel and CYP3A inhibitors. This phenomenon may be associated with worse outcomes in patients with the non-expressor genotype who are given clopidogrel after coronary angioplasty and implantation of bare-metal stents.

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Individual and joint use of statins and low-dose aspirin and risk of colorectal cancer: a population-based case-control study.

Recent research has drawn attention to protective effects of statins on colorectal cancer (CRC) and possible joint effects with other drugs. Because statins are often administered in combination with low-dose aspirin for the prevention of cardiovascular disease, the aim of our study was to investigate individual and combined effects of statins and low-dose aspirin on CRC risk. We assessed use of statins and low-dose aspirin in 540 cases with histologically confirmed incident CRC and 614 control subjects in a population-based case-control study in Germany. Multiple logistic regression was used to estimate the impact of regular use of either low-dose aspirin or statins, and of both drugs combined on CRC risk. We found modest risk reduction of CRC for regular use of low-dose aspirin (adjusted odds ratio 0.77, 95% confidence interval 0.55-1.07) and a stronger association with regular use of statins (OR 0.65, 95% CI 0.43-0.99) or use of both drugs (OR 0.63, 95% CI 0.36-1.10). Combined use of low-dose aspirin and statins was associated with risk reduction by 62% after 5 or more years (OR 0.38, 95% CI 0.15-0.97). Combinational chemoprevention with low-dose aspirin and statins might provide stronger risk reduction than either of the single drugs after at least 5 years use, but confirmation is needed, preferably in prospective cohort studies and eventually by randomized controlled trials.

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Concomitant Administration of Direct Oral Anticoagulants in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Tyrosine Kinase Inhibitors.

In the last decades, the chronic myeloid leukemia (CML) therapeutic landscape has changed dramatically with the introduction of tyrosine kinase inhibitors (TKIs), with 10-year survival rates improving to up to 80%. Long-lasting TKI treatment, in particular with second-generation TKIs, has enabled clinicians to manage the onset of several side effects and other co-morbidities, such as atrial fibrillation or venous thromboembolism (VTE). We retrospectively evaluated nine CML patients treated with TKIs between 2017 and 2020 who experienced atrial fibrillation or VTE and received concomitant administration of TKIs and direct oral anticoagulants (DOACs) outside clinical trials, to evaluate the efficacy and safety of this combination. Median age was 66 years at CML diagnosis (range 52-73 years) and 69 years at the time of starting DOACs. A female predominance was observed. The median follow-up of concomitant DOAC and TKI administration was 8.5 months; edoxaban was administered in six patients and apixaban in two patients, and one patient received rivaroxaban. Regarding CML treatment, four patients received imatinib, two patients bosutinib, and three nilotinib. In eight patients DOACs were started for atrial fibrillation and in one patient for VTE. In none of the patients treated with the combination were additional symptomatic thrombotic adverse events or major bleedings reported. In this small case series, the use of DOACs in CML patients seemed feasible. Additional data on long-term outcomes including a larger cohort of CML patients treated with DOACs are, however, needed.

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Exploring the impact of once-daily OROS® methylphenidate (MPH) on symptoms and quality of life in children and adolescents with ADHD transitioning from immediate-release MPH.

To explore the clinical and health-related quality of life (HRQoL) outcomes in children/adolescents with attention-deficit/hyperactivity disorder (ADHD) who required a therapy switch from immediate-release (IR) methylphenidate (MPH) and were initiated on Osmotic Release Oral System (OROS(®)) MPH. Prospective, noninterventional study including patients (aged 6-18 years) with a confirmed diagnosis of ADHD who transitioned from IR MPH to OROS(®) MPH based on medical needs. Patients were transitioned to OROS(®) MPH and were followed for 12 weeks. Attention-deficit/hyperactivity disorder symptoms, functional outcomes, HRQoL, and tolerability were assessed throughout the study. 598 patients entered the intention-to-treat analysis. The mean OROS(®) MPH starting dose was 29.5 ± 12.0 mg/day, increasing slightly to 33.5 ± 13.2 mg/day at final visit. Compared with baseline, there were significant (all P < 0.0001) symptomatic, functional, and HRQoL improvements after transitioning from IR MPH to OROS(®) MPH as assessed by the Conners' Parent Rating Scale (from 29.0 ± 10.5 to 19.5 ± 11.1), Children's Global Assessment Scale (by 11.0 ± 13.3), and Inventory for Assessing Quality of Life (ILC) LQ0-28 scores (parents' rating from 17.2 ± 3.9 to 19.4 ± 4.0; patients' rating from 18.7 ± 4.0 to 20.5 ± 3.9). Overall, no significant changes in quality of sleep or appetite were observed. More than 70% of parents and physicians rated the effectiveness of OROS(®) MPH as at least "good" and were at least "satisfied" with OROS(®) MPH. The most common treatment-emergent adverse events were insomnia and anorexia. No clinically relevant changes in body weight or vital signs were observed. In this naturalistic setting, transitioning from IR MPH to OROS(®) MPH, in patients who showed previously insufficient response and/or poor tolerability, was successful. Patients' and parents' HRQoL as well as burden of disease showed a clinically relevant improvement. OROS(®) MPH was generally safe and well tolerated.

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Twelve months of nightly zolpidem does not lead to dose escalation: a prospective placebo-controlled study.

To assess hypnotic self-administration and likelihood of dose escalation over 12 months of nightly use of zolpidem versus placebo in primary insomniacs. Randomized, double-blind, placebo-controlled, clinical trial. Outpatient with tri-monthly one-week, sleep laboratory assessments. Thirty-three primary insomniacs, without psychiatric disorders or drug and alcohol abuse, 32-64 yrs old, 14 men and 19 women. Participants were randomized to take zolpidem 10 mg (n = 17) or placebo (n = 16) nightly for 12 months. In probes during month 1, 4, and 12, after sampling color-coded placebo or zolpidem capsules on 2 nights, color-coded zolpidem or placebo was chosen on 5 consecutive nights and 1, 2, or 3 of the chosen capsules (5 mg each) could be self-administered on a given choice night. Zolpidem was chosen more nights than placebo (80% of nights) and number of nights zolpidem was chosen did not differ over the 12 months. More zolpidem than placebo capsules were self-administered, and the total number of placebo or zolpidem capsules self-administered did not differ as a function of duration of use. In contrast, the total number of placebo capsules self-administered by the placebo group increased across time. The nightly capsule self-administration on zolpidem nights did not differ from that on placebo nights and neither nightly self-administration rates increased over the 12 months. An average 9.3 mg nightly dose was self-administered. Zolpidem was preferred to placebo, but its self-administration did not increase with 12 months of use. Chronic hypnotic use by primary insomniacs does not lead to dose escalation.

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Comparison of the effects of hydrochlorothiazide and furosemide on lithium disposition.

This study examined the interaction between lithium and diuretics, comparing both the pharmacokinetic and the pharmacodynamic variable of hydrochlorothiazide, furosemide, and placebo. The study, which took place in an outpatient research clinic of a university hospital, used a double-blind, placebo-controlled crossover design. The subjects were normal, healthy male volunteers who responded to recruitment announcements. Thirteen subjects entered and completed the study. All subjects took lithium, 300 mg b.i.d., for 6 weeks. Hydrochlorothiazide, 25 mg b.i.d.; furosemide, 20 mg b.i.d.; and placebo were given during weeks 2, 4, and 6 in a random order of assignment. Serum lithium levels and indices of diuretic activity were measured during each week. The subjects' serum lithium levels after 5 days of taking hydrochlorothiazide were significantly higher than after 5 days of taking furosemide and placebo. At the doses studied, hydrochlorothiazide was also more potent than furosemide in increasing plasma renin activity, increasing sodium excretion, and decreasing lithium excretion. The observed differences between diuretics in effects on serum lithium may have been due to differences in the potency of the diuretics at the doses studied as well as in the site of action of the diuretic effect. The results must be interpreted cautiously, however, because the effects were small and of questionable clinical significance, and the study used healthy volunteers and low doses of lithium instead of psychiatric patients and the usual therapeutic levels of lithium.

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Safety profile of the direct oral anticoagulants: an analysis of the WHO database of adverse drug reactions.

Direct oral anticoagulants (DOACs) have shown noninferiority to warfarin for stroke prevention in nonvalvular atrial fibrillation (AF) and a more promising safety profile. Unanswered safety aspects remain to be addressed and available evidence on the risk associated with these drugs are conflicting. In order to contribute to the debate on their safety profile, we conducted a comparative analysis of the reports of suspected adverse drug reactions (ADRs) associated with DOACs in VigiBase. Study based on reports of suspected ADRs held in VigiBase as at December 2014, in which a DOAC or warfarin were administered in patients with nonvalvular AF and listed as suspected/interacting drugs. Medical Dictionary for Regulatory Activities was used to classify ADRs. Reporting odds ratio (ROR) with 95% confidence interval were calculated. Results with P ≤ 0.05 were statistically significant. We retrieved 32 972 reports. We identified 204 ADRs with a ROR >1 (P ≤ 0.05) and we focused on 105 reactions. Positive ROR emerged for DOACs and gastrointestinal haemorrhage compared with warfarin [(1.6 (1.47-1.75)], but no disproportionality with cerebral haemorrhage was found [0.31 (0.28-0.34)]. We identified other potential signals that have not been associated with DOACs previously. As well as premarketing authorization clinical trial studies, we found a reduced risk of intracranial haemorrhage, but an increased risk of gastrointestinal haemorrhage in patients treated with DOACs compared to warfarin. We provide new data and we highlight several differences between the three novel oral anticoagulants, in the rate and type of ADRs occurred.

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Long-term haemodynamic effects of amlodipine at rest and during exercise in essential hypertension.

The long-term haemodynamic responses to amlodipine, a new long-acting calcium antagonist, were studied both at rest and during exercise in 18 patients (mean age 43 years) with essential hypertension. Blood pressure was measured intra-arterially, cardiac output by dye dilution and heart rate by electrocardiogram. After 11 months of treatment with 5-10 mg amlodipine once daily (mean dose 9 mg/day), mean arterial pressure was reduced by 14% sitting at rest. The reduction in blood pressure was associated with a marked reduction in the total peripheral resistance index (TPRI) of 19% (P less than 0.001). Similar responses were seen supine at rest and during 50W, 100W and 150W bicycle exercise. No significant changes were seen in heart rate. There was a slight increase in stroke index, and cardiac index was preserved at rest and during exercise with a slight trend towards an increase. In 10 of the patients, blood pressure was monitored by a portable blood pressure recorder (Accutracker II, Suntech Medical instruments, Raleigh, North Carolina, USA). Blood pressure was well controlled throughout the full 24 h period after one daily dose. In conclusion, amlodipine exerts a clear antihypertensive effect, both at rest and during exercise, through reduction in the TPRI and without a fall in cardiac pump function. No changes in heart rate were seen and there was no tendency for a reduction in the stroke index during 8 min of exercise at 150 W; on the contrary there was a trend towards an increase. The incidence of side-effects was low (ankle oedema in two patients).

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The effect of a combination antacid preparation containing aluminium hydroxide and magnesium hydroxide on rosuvastatin pharmacokinetics.

Rosuvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor used for the treatment of dyslipidaemia, may be co-administered with antacids in clinical practice. This trial assessed the effect of simultaneous and separated administration of an antacid preparation containing aluminium hydroxide 220 mg/5 mL and magnesium hydroxide 195 mg/5 mL (co-magaldrox 195/220) on the pharmacokinetics of rosuvastatin. A randomised, open-label, three-way crossover trial was performed. Healthy male volunteers (n = 14) received a single dose of rosuvastatin 40 mg alone, rosuvastatin 40 mg plus 20 mL antacid suspension taken simultaneously, and rosuvastatin 40 mg plus 20 mL antacid suspension taken 2 h after rosuvastatin on three separate occasions with a washout of > or = 7 days between each. The primary parameters were area under the rosuvastatin plasma concentration-time curve from time zero to the last quantifiable concentration (AUC(0-t)) and maximum observed rosuvastatin plasma concentration (C(max)) in the absence and presence of antacid. When rosuvastatin and antacid were given simultaneously, the antacid reduced the rosuvastatin AUC(0-t) by 54% (90% confidence interval [CI] for the treatment 0.40-0.53) and C(max) by 50% (90% CI 0.41-0.60). When the antacid was given 2 h after rosuvastatin, the antacid reduced the rosuvastatin AUC(0-t) by 22% (90% CI 0.68-0.90) and the C(max) by 16% (90% CI 0.70-1.01). The effect of repeated antacid administration was not studied and it cannot be discounted that this may have resulted in a stronger interaction than that observed here. Simultaneous dosing with rosuvastatin and antacid resulted in a decrease in rosuvastatin systemic exposure of approximately 50%. This effect was mitigated when antacid was administered 2 h after rosuvastatin.

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A comparison of the angiotensin II antagonists valsartan and losartan in the treatment of essential hypertension.

We compared the angiotensin II receptor antagonist valsartan to losartan as an antihypertensive agent in an 8-week trial. Adults with uncomplicated essential hypertension (baseline seated diastolic blood pressure < 115 mm Hg and > or = 95 mm Hg) were randomized to receive 80 mg valsartan, 50 mg losartan, or placebo once daily. After 4 weeks doses of active medication and placebo were doubled. Seated systolic and diastolic blood pressures were measured and the response rate evaluated. Tolerability was assessed by the incidence of adverse events. Both angiotensin II receptor antagonists produced similar significant reductions in mean blood pressures at 4 and 8 weeks compared to placebo. Valsartan produced a significantly higher number of responders (62%) than losartan (55%, P = .02) at the 8 week treatment endpoint. The incidence of adverse experiences (AE) was similar in all three groups, with headache and dizziness reported most often. Valsartan (80/160 mg) monotherapy in this trial was as effective and well tolerated as 50/100 mg losartan in treating mild to moderate essential hypertension, and at 160 mg has a significantly higher responder rate than 100 mg losartan.

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Prospective study of efficacy and safety of lansoprazole in Zollinger-Ellison syndrome.

Lansoprazole, a new substituted benzimidazole H+,K(+)-ATPase inhibitor, profoundly inhibits gastric acid secretion and has potential use in the management of diseases such as Zollinger-Ellison syndrome (ZES). In the present study we evaluated the efficacy and safety of lansoprazole in controlling acid hypersecretion in 20 patients with ZES. The starting dose was 60 mg once daily. Control of acid hypersecretion was defined as the dose required to reduce acid secretion to < 10 meq/hr in the last hour before the next dose. Doses were adjusted upwards until effective control was achieved. Patients not controlled with 120 mg once daily were placed on twice daily lansoprazole. Most patients (90%) required lansoprazole once daily. During long-term follow-up (mean 18.5 months), 25% of patients required upward dose adjustments and 25% of patients required twice daily lansoprazole. Following cessation of therapy, the mean time for gastric acid output to reach half basal acid output was 39.1 hr. Lansoprazole was well-tolerated without side effects. Clinical chemistry and hematological studies were unchanged, and no gastric carcinoids developed. These results demonstrate that lansoprazole is a safe and effective inhibitor of gastric acid hypersecretion in patients with Zollinger-Ellison syndrome. Because it has a long duration of action, lansoprazole can be used to control gastric acid hypersecretion in most patients with Zollinger-Ellison syndrome using a once daily dosing schedule.

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Efficacy and safety of valsartan/amlodipine single-pill combination in 11,422 Chinese patients with hypertension: an observational study.

Single-pill combination (SPC) therapy of two drugs is recommended by international guidelines, including the Chinese guidelines (2010), for the treatment of hypertension in high-risk patients who require marked blood pressure (BP) reductions. Real-world data on the efficacy and safety of valsartan/amlodipine (Val/Aml) SPC are scarce. The present study is the first observational study in China to evaluate the efficacy (primary endpoint) and safety of Val/Aml (80/5 mg) SPC in Chinese patients with hypertension whose BP was not adequately controlled by monotherapy in a real-world setting. This prospective, multicenter, open-label, post-marketing observational study included 11,422 Chinese adults (≥18 years) with essential hypertension from 238 sites of 29 provinces who were prescribed once-daily Val/Aml (80/5 mg) SPC. Patients were treated for 8 weeks. The primary efficacy variable of the study included changes in mean sitting systolic BP (MSSBP) and mean diastolic BP (MSDBP) from baseline to week 8 (end point). The secondary efficacy variable of the study included BP control rate and response rate at week 4 and 8. Safety assessments included recording and measurement of all adverse events (AEs) and vital signs in the safety population. A significant reduction of 27.1 mmHg in MSSBP (159.6 vs. 132.5 mmHg; P < 0.0001) and 15.2 mmHg in MSDBP (95.6 vs. 80.4 mmHg; P < 0.0001) from baseline was observed at week 8. The BP-lowering efficacy of Val/Aml SPC was independent of age and comorbidities. BP control of <140/90 mmHg was achieved in 76.8% (n = 8,692) of the patients. The most frequently reported AEs were dizziness (0.2%), headache (0.2%), upper respiratory tract infection (0.2%), and edema (0.2%). Only three serious AEs were reported and they were not drug-related. This is the first evidence-based real-world data in Chinese hypertensive patients which demonstrate the efficacy and safety of Val/Aml (80/5 mg) SPC.

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Genotypic and functional roles of IL-1B and IL-1RN on the risk of gastroesophageal reflux disease: the presence of IL-1B-511*T/IL-1RN*1 (T1) haplotype may protect against the disease.

We aimed at evaluating the role of interleukin-1B (IL-1B) and IL-1RN polymorphisms, which may modulate the gastric mucosal expression of IL-1beta, thus altering acid secretion, which influences the severity of gastroesphageal reflux disease (GERD). In a prospective study, 144 patients with GERD (diagnosed by at least two of these criteria: Carlsson-Dent score of 6, endoscopic evidence of GERD, histopathological evidence of esophagitis, percentage time esophageal pH <4 for >5% on 24-h pH monitoring, and response to omeprazole 20 mg/day) and 368 healthy controls were genotyped for IL-1B-511 C/T and IL-1RN VNTR polymorphism (by PCR-restriction fragment length polymorphism (RFLP) and PCR, respectively). Gastric mucosal IL-1beta levels (picogram/milligram of biopsy sample) were measured (using enzyme-linked immunosorbent assay (ELISA)) in 71 patients. Helicobacter pylori diagnosis was conducted using anti-H. pylori immunoglobulin G (IgG) ELISA. Patients (41.1+/-13.3 years old, 96 (66.7%) men) were comparable with healthy controls (43.4+/-11.8 years old, 238 (64.7%) men) with respect to age and gender. The IL-1B-511 CC genotype and C allele were associated with higher risk of GERD than the TT genotype (P=0.01, odds ratio (OR)=2.0, 95% confidence interval (CI)=1.12-3.57) and the T allele (P=0.04, OR=1.3, 95% CI=1.0-1.7), respectively. TT and C noncarriers had more IL-1beta than CT (33.2 (2.6-161.3) vs. 16.7 (2.8-121.9), P=0.04) and C carriers (33.2 (2.6-161.3) vs. 15.16 (1.5-121.9), P=0.04), respectively. IL-1RN "1,2" and "2 carriers" had higher risk (P<0.001, OR=2.0, 95% CI=1.31-3.1; P=0.01, OR=1.6, 95% CI=1.1-2.4, respectively). "2,2" Had lower IL-1beta levels than both "1,1" and "1,2" (9.2 (1.5-70.7) vs. 26.8 (5.7-161.3), P=0.006; 9.2 (1.5-70.7) vs. 24.4 (2.6-78.0), P=0.02). However, "2 carriers" tended to have lower IL-1beta levels than "2 noncarriers" (21.7 (1.5-78.0) vs. 26.8 (5.7-161.3), P=0.09). The IL-1B-511*T/IL-1RN*1 ("T1") haplotype showed lower risk (P=0.05, OR=0.7, 95% CI=0.5-1.0). "T1" had higher IL-1beta levels than both "T1 carriers" and "T1 noncarriers" (43.5 (18.2-161.3) vs. 23.9 (2.6-121.9), P=0.02; 43.5 (18.2-161.3) vs. 10.9 (1.5-82.6), P=0.06, respectively). The presence of H. pylori infection was associated with the stronger risk of the IL-1B-511*CC genotype. The "T1" haplotype was strongly protective against GERD among patients with H. pylori infection. The T1 haplotype was associated with the reduced risk of GERD, particularly among patients with H. pylori infection, probably because of higher gastric mucosal IL-1beta levels.

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Erythema migrans in the immunocompromised host.

From 1990 to 1996 a total of 67 adult patients with typical erythema migrans (EM) and a previously identified immunocompromised condition were investigated at the University Medical Centre, Department of Infectious Diseases, Ljubljana, Slovenia. The course and outcome of borrelial infection were compared with 67 previously healthy age and sex-matched individuals with EM who were examined at our institution in the same year. Clinical characteristics of Lyme borreliosis before treatment and the duration of EM after the institution of therapy with antibiotics including amoxicillin, azithromycin, cefuroxime-axetil, doxycycline, and ceftriaxone were comparable in both groups. The occurrence of early disseminated borrelial infection before treatment and the frequency of treatment failure (defined as the onset of severe minor or major manifestations of Lyme borreliosis, persistence of B. burgdorferi sensu lato in the skin and/or persistence of EM after treatment) were found significantly more often in immunocompromised patients than in the control group (16/67 versus 6/67, respectively; p = 0.0358). Re-treatment was required in 13 (19.4%) patients of the immunocompromised group and only in five (7.5%) patients of the control group (p = 0.0762). However, in spite of the more severe course and the more frequent need for re-treatment among patients whose immune system was impaired, the outcome of borrelial infection after one year was favourable in both groups.

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Effects of short-term stimulation of serotoninergic pathways on the pulsatile secretion of luteinizing hormone in the absence and presence of acute opiate-receptor blockage.

To investigate the role of the serotoninergic system in regulating pulsatile gonadotropin secretion in man, we tested the influences of a novel selective serotonin re-uptake inhibitor (fluoxetine HCl) on episodic LH release in men. Spontaneous LH pulsatility was assessed by computerized analysis of serial LH concentrations measured in blood samples withdrawn at 10 min intervals for 24 h. Possible alterations in pituitary responsiveness were tested by administering three consecutive two-hourly intravenous pulses of GnRH (10 micrograms, 10 micrograms, and 100 micrograms). The effects of fluoxetine (20 mg orally three times daily for one wk) were assessed in a double-blind, placebo-controlled design. Compared with the placebo, fluoxetine elicited no changes in 24 h mean serum LH concentrations, LH pulse characteristics (Cluster analysis), or LH secretion and clearance parameters assessed in response to exogenous GnRH administration (deconvolution analysis) in the presence of normal opiatergic tone (nine healthy young men), and during acute blockade of the opiatergic system (seven young men treated with the mu-opiate receptor antagonist, naltrexone). In summary, a selective enhancer of serotoninergic activity (fluoxetine HCl) does not affect pulsatile LH release basally or in the presence of acute inhibitory opiatergic tone. Since this probe does modify prolactin secretion in man, we conclude that stimulation of the serotoninergic system by this selective neuroendocrine probe shows no demonstrable coupling between the serotoninergic and the opiatergic pathways that modulate pulsatile LH release in man.

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Exploring Medication Adherence with P2Y₁₂ Inhibitors Using Conditional and Unconditional Quantile Regression Approaches.

Previous research assessing medication adherence with P2Y₁₂ inhibitors has shown good adherence rates, ranging from 78% to 92%. Studies that used administrative claims data defined adherence using an arbitrary cut point of ≥ 80% medication possession ratio (MPR) or proportion of days covered (PDC). While this method is used frequently, it does not allow the researcher to observe how each factor impacts adherence along the entire distribution. The objective of the study was to use conditional quantile regression (CQR) and unconditional quantile regression (UQR) to assess heterogenous effects of adherence to P2Y₁₂ inhibitors and covariates of interest and compare these results to those from a traditional logistic regression framework. This study used the commercial claims and encounters databases from IBM^® MarketScan^® from 2010 to 2017. We included patients who had an incident percutaneous coronary intervention, used a drug-eluting stent, and filled an incident prescription for a P2Y₁₂ inhibitor. Adherence was measured for 185 days using PDC. Adherence to branded clopidogrel, generic clopidogrel, branded prasugrel, and branded ticagrelor was assessed, along with factors that could impact adherence, using logistic regression, CQR, and UQR. We found that while adherence to the antiplatelets was generally high, prasugrel and ticagrelor had significantly lower PDC compared to branded clopidogrel, especially around the 30th percentile. Across all quantiles in both the CRQ and UQR frameworks, comorbidities such as diabetes and depression and living in the southern region had significant negative effects on adherence, although the relative impact differed across quantiles. Using CQR and UQR allowed for heterogenous assessment of covariates along the adherence distribution, which is not possible with the traditional logistic regression method. The UQR framework revealed patients who initiate prasugrel or ticagrelor generally have lower adherence compared to those treated with branded clopidogrel, especially around the 30th quantile. Using these methods in other types of data sets, such as electronic health records, could help strengthen our results to develop policies to improve antiplatelet adherence in a targeted population.

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Hot executive control and response to a stimulant in a double-blind randomized trial in children with ADHD.

Attention deficit hyperactivity disorder (ADHD) is thought to involve an executive inhibitory control (IC) deficit, yet it is not clear if this is a general deficit affecting both cold and hot EC, and if methylphenidate (MPH) affects both systems in treated children. We explored this by using a Stroop-like task in children with ADHD as compared to controls, containing different types of emotional stimuli (six levels), and we investigated the role of intervention with MPH on IC as compared to placebo. Children with ADHD and controls (N = 40; 7-13 years old) were tested with a hot and cold Stroop-like task. This was followed by a double-blind placebo-controlled crossover trial of the effect of MPH on these skills. Children with ADHD showed a specific difficulty inhibiting their responses, particularly to hot, angry and frustration-inducing stimuli. Further, treatment with MPH was effective in reducing errors toward frustration-inducing stimuli as compared to placebo (p < .05, η ² = .347), particularly with repeated exposure to the stimuli. Results indicate that children with ADHD experience executive control difficulties, particularly in hot negative emotional contexts. These emotion regulation difficulties are amenable to stimulant intervention.

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In-utero exposure to metformin for type 2 diabetes or polycystic ovary syndrome: A prospective comparative observational study.

To evaluate the rate of major anomalies after first trimester (T1)-metformin exposure. Comparative, observational cohort study done at the Israeli Teratology Information Service between 2000 and 2013. 170 T1-metformin-exposed pregnancies [119 for diabetes and 51 for polycystic ovary syndrome (PCOS)] were prospectively followed-up and compared with 93 pregnancies of T1-insulin treated women and 530 non-teratogenic exposed (NTE) pregnancies. The differences in the rate of major anomalies excluding genetic/cytogenetic, and spontaneously resolved cardiovascular anomalies were not significant [4.4% (2/45) - metformin-PCOS, 1.1% (1/90) - metformin-diabetes, 2.5% (2/80) - insulin, and 1.7% (9/519) - NTE; OR_{adj metformin}/_NTE 1.77; 95% CI 0.45-7.01; OR_{adj insulin}/_NTE 1.69; 95% CI 0.35-8.11]. The rate of Cesarean section was higher in both the metformin-diabetes 51/90 (56.7%) and insulin 45/79 (57.0%) groups compared with the NTE group [138/503 (27.4%)]. Metformin-T1-exposure per se is not associated with an increased risk of major anomalies.

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Gabapentin-related Deaths: Patterns of Abuse and Postmortem Levels.

Gabapentin, a GABA analogue, is a nonopioid prescribed for seizure control and neuralgic pain. Its abuse for recreational purposes has been increasing in recent years as the number of prescriptions also increases. In our series, we review 104 cases of decedents who tested positive for gabapentin in postmortem blood samples and an additional 53 nonfatal cases of motor vehicle drivers suspected of driving under the influence. In 47.1% of the fatality cases, gabapentin was directly involved in death. Most gabapentin fatalities had several other intoxicants present (opioids, over-the-counter medications, antianxiety, and antidepressant medications). In cases in which gabapentin was determined to be a cause of death, the blood concentrations ranged from 1.1 to 134.0 mg/L. Persons who died of a gabapentin-related drug death were prescribed the drug legitimately 91.4% of the time, with 84.2% of those also having a known prior history of abuse or misuse of prescription medications.

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Comparison of olmesartan combined with a calcium channel blocker or a diuretic in elderly hypertensive patients (COLM Study): safety and tolerability.

The cardiovascular effects of combined therapy with the angiotensin receptor blocker (olmesartan) and a dihydropyridine calcium channel blocker (CCB) or a diuretic were compared in high-risk elderly Japanese hypertensive patients by performing a randomized, open label, blinded-endpoint study of morbidity and mortality (the COLM study). Here we report the results obtained with respect to safety and tolerability. High-risk hypertensive patients aged 65-84 years were enrolled and were randomized to receive olmesartan combined with either a CCB (amlodipine or azelnidipine) or a low-dose diuretic for at least 3 years. The primary endpoint was a composite of fatal and non fatal cardiovascular events, whereas adverse events (AEs) and the percentage of patients who discontinued the allocated treatment were evaluated as secondary endpoints. A total of 5141 patients were randomized. Both combination regimens achieved a similar reduction of cardiovascular morbidity and mortality. The incidences of AEs, serious AEs, drug-related serious AEs and discontinuation due to serious AEs were lower in the olmesartan plus CCB group than in the olmesartan plus diuretic group. Serum levels of uric acid and creatinine were significantly higher in the olmesartan plus diuretic group than in the olmesartan plus CCB group. Olmesartan combined with a CCB was significantly superior to olmesartan plus a diuretic with regard to the frequency of AEs and discontinuation of treatment.

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Syncytial giant cell hepatitis in human immunodeficiency virus-infected patients with chronic hepatitis C: 2 cases and review of the literature.

Syncytial giant cell hepatitis (SGCH) among adult human immunodeficiency virus (HIV)-infected patients has been rarely described. Most cases have been reported in subjects coinfected with the hepatitis C virus (HCV), but its prevalence and outcome remain unknown. We performed a retrospective analysis of all cases of SGCH among 332 liver biopsies from HIV-infected patients seen at a tertiary center in Madrid, Spain, between 1984 and March 2004. Two hundred fifty specimens were obtained from HCV-coinfected patients. There were 2 cases of SGCH, leading to an observed overall prevalence of 0.6% (0.8% when considering only HCV-coinfected patients). In addition to histological changes secondary to chronic hepatitis C, the liver cords were replaced by syncytial giant cells with up to 30 nuclei. There was no histological evidence of measles (among paramyxoviruses) or herpes viruses group infections. In patient 1, there was a progressive clinical worsening after a 3-month course of prednisone, leading to liver failure and death. His postmortem liver biopsy showed more abundant giant hepatocytes accompanied with the development of a histologic pattern of severe fibrosing cholestatic hepatitis. The second patient received a prolonged course of pegylated interferon-alpha-2b and ribavirin with clearance of syncytial giant hepatocytes despite HCV-RNA persistence. SGCH is a rare histological finding among HIV-infected patients with chronic hepatitis C. Specific treatment with pegylated interferon and ribavirin can lead to histological resolution and biochemical improvement, even in the absence of HCV-RNA clearance.

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Angiotensin converting enzyme inhibition worsens the excretory phase of diuretic renography for obstructive hydronephrosis.

A growing body of evidence identifies the renin-angiotensin system as a key factor in the onset and progression of renal damage in chronic partial obstruction, which often represents a complex diagnostic challenge. A prospective study was undertaken to evaluate the role of captopril mercaptoacetyltriglycine-3 (MAG-3) renography as an early diagnostic test of obstruction. We report the results in a subgroup of children who underwent surgical correction for pyeloureteral obstruction. Pyeloplasty was performed in 12 patients, including 10 males, 2 to 72 months old (median age 7) with unilateral hydronephrosis, including normal renal function and blood pressure. Basal and captopril enhanced diuretic renography with 99mtechnetium MAG-3 was performed within 24 hours using the same hydration and diuretic stimulus (0.75 mg./kg. furosemide), and 0.75 mg./kg. captopril was administered orally 60 to 90 minutes before scintigraphy. No adverse effects or modifications of the blood pressure were observed after captopril administration. The diuretic response was deeply worsened by angiotensin converting enzyme inhibition in each hydronephrotic kidney even when the basal study was only slightly abnormal (15-minute washout basal -27 +/- 16%, after captopril -9 +/- 13, p <0.005). After surgical correction the diuretic washout during angiotensin inhibition appeared normal in all patients (15-minute washout -56 +/- 14%). Separate renal function and parenchymal transit of MAG-3 were not modified by angiotensin converting enzyme inhibition, preoperatively or postoperatively. Our data confirm the influence of angiotensin on the kidney excretory system in human hydronephrosis and suggest a role for captopril enhanced diuretic renography in the early diagnosis of pyeloureteral obstruction. Further work is needed to evaluate angiotensin converting enzyme inhibition as a protective agent in obstructive nephropathy.

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Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome-thrombolysis in myocardial infarction 51 (ATLAS-ACS 2 TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome.

Although therapy with aspirin or aspirin plus a thienopyridine reduces the incidence of long-term adverse cardiovascular events among patients with acute coronary syndrome (ACS), there remains a significant residual risk of cardiovascular death, recurrent myocardial infarction (MI), and stroke. In a phase 2 trial (ClinicalTrials.gov NCT00402597) in which the addition of the factor Xa inhibitor rivaroxaban was compared with placebo, among ACS patients receiving either aspirin alone or dual-antiplatelet therapy with aspirin and a thienopyridine, the end point of death, MI, or stroke compared with placebo was reduced (87/2331 [3.9%] vs 62/1160 [5.5%]; hazard ratio 0.69, [95% CI 0.50-0.96], P = .027). Two candidate doses of rivaroxaban were selected for further evaluation in a pivotal phase 3. The second ATLAS-ACS 2 TIMI 51 Trial is an international, randomized, double-blind, event-driven (n = 983) phase 3 trial involving more than 15,570 patients hospitalized with ACS (ClinicalTrials.gov NCT00809965). All patients are treated with a background of standard therapy including low-dose aspirin, and patients are stratified by the administration of a thienopyridine (clopidogrel or ticlopidine; stratum 2) or not (stratum 1). Within each stratum, patients are randomly assigned in a 1:1:1 ratio to receive rivaroxaban 2.5 mg twice daily, or rivaroxaban 5 mg twice daily, or placebo twice daily. The primary efficacy end point is the composite of cardiovascular death, MI, or stroke. The primary safety end point is thrombolysis in MI major bleeding not associated with coronary artery bypass graft surgery. The ATLAS-ACS 2 TIMI 51 is testing the hypothesis that anticoagulation with the oral factor Xa inhibitor rivaroxaban reduces cardiovascular death, MI, and stroke among patients with ACS treated with guideline-based therapies for ACS.

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Eradication Rate by Duration of Third-line Rescue Therapy with Levofloxacin after Helicobacter pylori Treatment Failure in Clinical Practice.

This study evaluated the eradication rate of levofloxacin-containing rescue therapy by treatment duration in patients in whom previous first- and second-line treatment failed. Fifty-five patients with persistent <i>Helicobacter pylori</i> infection after first-line therapy and second-line therapy were studied in a single referral academic center. We compared the eradication rates by the treatment duration of third-line therapy. Of 55 patients, 12 (21.8%) received rescue therapy for seven days, 24 (43.6%) received rescue therapy for 10 days, and 19 (34.5%) received rescue therapy for 14 days. The eradication rates of therapy with levofloxacin were 65.5% in the 55 enrolled patients and 73.5% in the 49 patients who underwent follow-up testing. In cases where follow-up testing was performed, the eradication rate of 7-day therapy was 58.3%, of 10-day 68.2%, and of 14-day therapy 93.3%. Eradication rate of 14-day therapy was higher than 7-day (p=0.06) and 10-day (p=0.108), but chance could not be ruled out in the difference among groups. This study showed somewhat increasing of <i>H. pylori</i> eradication rate by extending the duration of levofloxacin-containing rescue therapy to 14 days.

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Identification of clinical predictors of flare in systemic lupus erythematosus patients: a 24-month prospective cohort study.

SLE has a relapsing-remitting course with disease activity flares over time. This study aims to identify clinical predictors of SLE flares. This prospective cohort study over 24 months included all SLE patients on follow-up at one academic lupus clinic. Flare was defined as an increase in SLEDAI-2K score ≥4 points. Baseline clinical and demographic parameters were compared using survival analysis for time-to-flare outcome with univariate log-rank tests. Variables with significant differences were further evaluated as predictors with multivariate Cox regression models adjusting for potential confounding or contributing factors and hazard ratio (HR) calculation. A total of 202 SLE patients were included. Over the follow-up period, 1083 visits were documented and 16.8% of patients presented with flares. In multivariate analysis, the following parameters emerged as flare predictors: SLE diagnosis up to 25 years of age (HR = 2.14, P = 0.03), lupus nephritis previous to baseline visit (HR = 4.78, P < 0.0001) and immunosuppressor treatment for severe SLE (HR = 3.22, P < 0.001). Baseline disease activity, disease duration and treatment with prednisone or HCQ were not predictive factors. Patients with an SLE diagnosis before age 25 years, lupus nephritis or immunosuppressor treatment for severe SLE present greater HRs for flares, suggesting the need for tighter clinical monitoring. Current immunosuppressive strategies seem to be inefficient in providing flare prevention.

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Effects of antileukotriene among asthmatic patients.

To determine the effect of antileukotriene (montelukast) 10 mg once daily for the treatment of mild to moderate asthma. Open label, prospective. Thirty asthmatic patients > or = 18 years of age with baseline FEV1 > 60 per cent and < or = 80 per cent of predicted values and evidence of reversible airway obstruction, as defined by an increase in FEV1 of > or = 20 per cent. Montelukast 10 mg once daily orally for 12 weeks, back up beta-2 agonist inhaler was available. Spirometry was performed during the screening period, and every month after starting antileukotriene. Subjects recorded asthma-related symptoms and use of supplement beta-2 agonists daily on diary cards. Over 12 weeks of treatment, the FEV1 increased 10 per cent, 14 per cent and 19 per cent respectively, compared to the baseline (p < 0.05). The physician and patients evaluation scores were quite good in the study. Oral montelukast once daily gave a favorable effect in management of mild to moderate asthmatic patients.

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Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products.

To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [< 30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥ 30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p = 0.362). No differences were identified in transfusions 6 h prior (p = 0.087) or 12 h after (p = 0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p = 0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

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Effect of antihypertensive formulation on health service expenditures.

A major barrier to the management of hypertension is the extent to which patients comply with the treatment regimen. Herein we report the findings of a retrospective analysis designed to discern the relationship between antihypertensive formulation, regimen compliance and the utilization of health care services. Data for this analysis were derived from the state of South Carolina's Medicaid computer archive. The study population consisted of 1,000 randomly selected beneficiaries initially prescribed one of the following antihypertensive regimens as monotherapy: atenolol (daily); captopril (twice daily); oral clonidine (twice daily); transdermal clonidine (once a week); diltiazem (twice daily); enalapril (twice daily); metoprolol (twice daily); prazosin (twice daily); terazosin (daily); and verapamil-SR (daily). Multivariate regression analysis was used to determine the incremental influence of selected demographic characteristics, utilization of medical services prior to diagnosis for hypertension, initial antihypertensive medication, medication possession ratio for antihypertensive therapy, and the number of maintenance medications for disease state processes other than hypertension on post-period health care expenditure. Results indicate that patients initially prescribed antihypertensive medication requiring daily or weekly administration experience infrequent changes in their therapeutic regimen, far less use of concomitant therapy for blood pressure control, an increased utilization of antihypertensive medication, and a decrease in the use and cost of physician, hospital and laboratory services.

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Tocilizumab in giant cell arteritis: Multicenter open-label study of 22 patients.

To assess the efficacy of tocilizumab (TCZ) in giant cell arteritis (GCA) patients with refractory disease and/or with unacceptable side effects due to corticosteroids. A retrospective multicenter open-label study on 22 GCA patients treated with TCZ at standard dose of 8mg/kg/month. The main outcomes were achievement of disease remission and reduction of corticosteroid dose. The mean age ± standard deviation of patients was 69 ± 8 years. The main clinical features at TCZ onset were polymyalgia rheumatica (n = 16), asthenia (n = 7), headache (n =5), constitutional symptoms (n = 4), jaw claudication (n = 2), and visual loss (n = 2). Besides corticosteroids and before TCZ onset, 19 of 22 patients had also received several conventional immunosuppressive and/or biologic drugs. Of 22 patients, 19 achieved rapid and maintained clinical improvement following TCZ therapy. Also, after a median follow-up of 9 (interquartile range: 6-19) months, the C-reactive protein level had fallen from 1.9 (1.2-5.4) to 0.2 (0.1-0.9)mg/dL (p < 0.0001) and the erythrocyte sedimentation rate decreased from 44 (20-81) to 12 (2-20)mm/1st hour (p = 0.001). The median dose of prednisone was also tapered from 18.75 (10-45) to 5 (2.5-10)mg/day (p < 0.0001). However, TCZ had to be discontinued in 3 patients due to severe neutropenia, recurrent pneumonia, and cytomegalovirus infection. Moreover, 1 patient died after the second infusion of TCZ due to a stroke in the setting of an infectious endocarditis. TCZ therapy leads to rapid and maintained improvement in patients with refractory GCA and/or with unacceptable side effects related to corticosteroids. However, the risk of infection should be kept in mind when using this drug in patients with GCA.

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Randomized study of different 'second-line' therapies for Helicobacter pylori infection after failure of the standard 'Maastricht triple therapy'.

Triple therapy with proton pump inhibitor, clarithromycin and amoxicillin and, in the event of eradication failure, quadruple therapy with proton pump inhibitor, bismuth, tetracycline and metronidazole have been proposed in Maastricht as the optimal sequential treatment of Helicobacter pylori infection. To compare two second-line regimens with quadruple therapy. One hundred and eighty patients with a previous failed course of standard therapy were randomly given one of the following 7-day treatments: ranitidine bismuth citrate 400 mg b.d. plus amoxicillin 1 g b.d. and tinidazole 500 mg b.d. (RBCAT), pantoprazole 40 mg b.d. plus amoxicillin 1 g b.d. and levofloxacin 500 mg/day (PAL) and pantoprazole 40 mg b.d., bismuth citrate 240 mg b.d., tetracycline 500 mg q.d.s. and metronidazole 500 mg b.d. (PBTM). The eradication rate was assessed by 13C-urea breath test. Side-effects and compliance were evaluated by a standardized questionnaire and by counting returned medication. The RBCAT, PAL and PBTM groups achieved mean intention-to-treat eradication rates of 85%, 63% and 83%, respectively (P<0.05 for PAL vs. either RBCAT or PBTM). Compliance was optimal in all patients, although side-effects were more commonly observed in the PBTM group than in the other two patient groups (P<0.0001). Both RBCAT and PBTM can be used as second-line therapies. Conversely, PAL did not achieve satisfactory eradication rates.

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An open-label study of the safety and tolerability of converting stable liver transplant recipients to neoral.

Neoral is a new formulation of cyclosporine based on microemulsion technology, designed to provide increased and more reliable absorption of the medication. The aim of this study was to assess whether conversion from Sandimmune to Neoral provides safe and effective oral immunosuppression in stable liver transplant recipients. We studied 59 stable liver transplant recipients (being treated with prednisone, azathioprine, and Sandimmune). All patients were enrolled in an open-label study in which they were converted from Sandimmune to Neoral therapy at a dose ratio of 1:1. Thirty-nine patients underwent duct-to-duct bile duct anastomoses, and 20 underwent Roux-en-Y bile duct anastomoses. After conversion, the Neoral dosage was adjusted on the basis of trough levels measured at weeks 1, 2, 3, 4, 6, 8, and 12. To assess safety and tolerability, we prospectively obtained serial information, including laboratory data and information on side effects. Standard statistical methodology was used. A total of 59 patients (23 men, 36 women; mean age, 55 years; mean follow-up after liver transplantation, 5.7 years) completed 3 months of follow-up after conversion from Sandimmune to Neoral. There were 32 dosage changes; 22 (69%) required reduction of the Neoral dose. Mean cyclosporine trough levels remained above 100 ng/mL during the follow-up period. There were no significant differences between cyclosporine levels in patients with duct-to-duct or Roux-en-Y bile duct anastomoses. There were no episodes of rejection during the 3-month follow-up period. The side effect profile was similar in both groups, except for a significant reduction in the number of patients with headaches after Neoral conversion. Liver transplant recipients can safely be converted from Sandimmune to Neoral. Neoral was well tolerated in this population.

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Rabbit antithymocyte globulin decreases acute rejection after lung transplantation: results of a randomized, prospective study.

The efficacy of antithymocyte induction therapy in lung transplantation is controversial, and its use varies from center to center. We hypothesized that rabbit antithymocyte globulin (RATG) induction therapy would decrease acute rejection after lung transplantation, and we designed a single-center, randomized, prospective study to test this hypothesis. A total of 44 single or bilateral adult lung transplant recipients were randomly assigned to receive either RATG induction therapy (dosage, 1.5 mg/kg/d for 3 days) at the time of transplantation, along with conventional immunosuppression (cyclosporine, azathioprine, and prednisone), or conventional immunosuppression alone with no induction therapy. Although a similar number of biopsies were performed in each group, the number of patients experiencing biopsy-proven grade II or greater acute rejection was significantly reduced in the group receiving RATG induction therapy (23% incidence), as compared to the patients treated with conventional immunosuppression alone (55% incidence; p = 0.03). In addition, there was a nonsignificant reduction in the incidence of bronchiolitis obliterans syndrome at the conclusion of the study in patients who received RATG induction (20%), as compared to patients in the control group (38%). The incidence of posttransplant infections and malignancies were similar between the two groups. Induction therapy with RATG significantly reduces the incidence of acute allograft rejection after lung transplantation.

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Structural imaging in late-life depression: association with mood and cognitive responses to antidepressant treatment.

Recent positron emission tomography studies of cerebral glucose metabolism have identified the functional neural circuitry associated with mood and cognitive responses to antidepressant treatment in late life depression (LLD). The structural alterations in these networks are not well understood. The present study used magnetic resonance (MR) imaging and voxel-based morphometry to evaluate the association between gray matter volumes and changes in mood symptoms and cognitive function with treatment with the antidepressant citalopram. Open-label trial with baseline brain MR scan. Mood and cognitive assessments performed at baseline and during citalopram treatment. Outpatient clinics of an academic medical center. 17 previously unmedicated patients age 55 years or older with a major depressive episode and 17 non-depressed comparison subjects. 12-week trial of flexibly dosed citalopram. Gray matter volumes, Hamilton Depression Rating Scale, California Verbal Learning Test, Delis-Kaplan Executive Function System. In LLD, higher gray matter volumes in the cingulate gyrus, superior and middle frontal gyri, middle temporal gyrus, and precuneus was associated with greater mood improvement. Higher gray matter volumes in primarily frontal areas were associated with greater improvement in verbal memory and verbal fluency performance. Associations with antidepressant induced improvements in mood and cognition were observed in several brain regions previously correlated with normalization of glucose metabolism after citalopram treatment in LLD. Future studies will investigate molecular mechanisms underlying these associations (e.g., beta-amyloid, inflammation, glutamate).

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Why do we need a statin trial in hemodialysis patients?

The risk of cardiovascular complications is markedly increased in patients on dialysis treatment. This includes cardiac disease, stroke, and peripheral vascular disease. The mortality in dialysis patients is markedly higher compared to a nonuremic population. There are several cardiovascular (CV) risk factors that are unique to this population, one of which is dyslipidemia. Uremic patients do not usually develop hypercholesterolemia, but rather are characterized by high levels of very low density lipoprotein (VLDL) triglycerides, low high density lipoprotein (HDL) cholesterol, and elevated levels of modified low density lipoprotein (LDL) particles, which are particularly harmful to the vascular wall. HMG-CoA reductase inhibitors (statins) have been proven to be very efficient in reducing CV events in a nonrenal population. There are several landmark trials that have demonstrated that statins reduce the mortality in cardiovascular disease (CVD) in populations with normal, or close to normal, renal function. There are some observational registry data indicating that this may also be true in hemodialysis (HD) patients, but no prospective controlled trial has been performed to date. We present the rationale for, and a brief outline of, a randomized placebo-controlled trial using a novel drug, rosuvastatin, in HD patients, to target cardiovascular events (the AURORA study). This study will include close to 3000 male and female HD patients, aged 50-80 years. The study is event driven and it has been estimated that it will run for a follow-up time close to four years. There is a sound rationale for making a randomized placebo-controlled statin trial in HD patients, with the objective to demonstrate an effect on CV mortality and morbidity.

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Differential effects of carvedilol and metoprolol on renal function in patients with heart failure.

The aim of the present study was to verify the effects of beta-blockers on renal function in patients with heart failure (HF). A total of 40 patients with HF (New York Heart Association class, II-III) were enrolled, who had beta-blocker therapy initiated with carvedilol (n=23) or metoprolol (n=17). The changes in renal and cardiac function were retrospectively analyzed over 16 weeks. The study population was divided into 2 groups according to the median baseline (65.9 ml/min) of estimated glomerular filtration rate (eGFR) calculated by the Modification of Diet in Renal Disease formula. eGFR significantly decreased in the higher eGFR group (P=0.04), but did not in the lower eGFR group. Left ventricular ejection fraction significantly increased in both groups with lower eGFR (P=0.01) and higher eGFR (P<0.01). There was an interaction between plasma norepinephrine concentration and eGFR in terms of beta-blocker treatment (P=0.02, ANOVA). eGFR significantly decreased in patients who received metoprolol (from 75.7+/-33.5 to 59.5+/-20.0 mlxmin(-1).1.73 m(-2), P<0.01), but did not change in those who received carvedilol (from 67.1+/-27.7 mlxmin(-1).1.73 m(-2) to 65.6+/-23.2 mlxmin(-1).1.73 m(-2)). Beta-blockers preserved renal function in HF patients with lower baseline eGFR, but not in those with higher baseline eGFR. Carvedilol may be preferable to metoprolol to prevent the development of chronic kidney disease during beta-blocker therapy for HF.

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Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during long-term acid-suppressive treatment in Japan.

Several studies have shown that acid-suppressive therapy aggravates corpus gastritis in patients with Helicobacter pylori infection, promoting the development of atrophic gastritis. To study the effects of long-term use of antisecretory agents on the H. pylori-positive gastric mucosa in Japan, a country with a high incidence of gastric cancer. A total of 141 H. pylori-positive patients who had peptic ulcers or reflux oesophagitis were treated for 3 years with either omeprazole (20 mg/day) alone (n=7) or with omeprazole for primary therapy (8 weeks), followed by famotidine (40 mg/day) for maintenance therapy (n=134). Endoscopy was performed before, during, and after treatment. Biopsy specimens were taken from the greater curvature of the antrum and corpus and were examined histologically. The long-term use of famotidine after 8 weeks of treatment with omeprazole distinctly decreased H. pylori density and neutrophil infiltration in the antrum, but did not change H. pylori density in the corpus. The gastritis score increased in patients who had no, or only mild corpus gastritis before treatment (n=74), and significantly decreased in those who had moderate or severe gastritis before treatment (n=60). In four of the seven patients who received long-term treatment with omeprazole alone, neutrophil infiltration and H. pylori density decreased not only in the antrum but also in the corpus. There was no increase in intestinal metaplasia or mucosal atrophy as assessed endoscopically during follow-up. Changes in corpus gastritis in response to acid-suppressive therapy depend on the severity of gastritis before treatment. Long-term use of acid-suppressive therapy apparently does not accelerate the development of atrophy or intestinal metaplasia in Japanese patients.

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Pharmacodynamic effect of switching therapy in patients with high on-treatment platelet reactivity and genotype variation with high clopidogrel Dose versus prasugrel: the RESET GENE trial.

High on-treatment platelet reactivity (HTPR) is associated with adverse outcomes. We aim to compare the novel thienopyridine prasugrel versus double-dose clopidogrel in patients with HTPR and explore the interaction between CYP2C19 genotype and both drugs. Consecutive stable patients undergoing percutaneous coronary intervention were screened with the Multiplate Analyzer P2Y12 assay, defining HTPR as area under the curve >450. Those with HTPR were randomized to prasugrel (10 mg/day) or high-dose clopidogrel (150 mg/day) for 2 weeks and then crossed-over to, respectively, clopidogrel and prasugrel, repeating the P2Y12 assay at the end of each cycle. Clinical follow-up (until 3 months) and CYP2C19 genotyping was performed in all patients. The primary end point was platelet reactivity after 14 days of prasugrel versus high-dose clopidogrel. Thirty-two patients were randomized to prasugrel and then high-dose clopidogrel or to high-dose clopidogrel followed by prasugrel. Prasugrel was associated with a significantly lower platelet reactivity than high-dose clopidogrel was (325.8 versus 478.5 area under the curve, P=0.028). No patient treated with prasugrel exhibited HTPR, whereas 9 (28.1%) receiving high-dose clopidogrel still had prevalence of HTPR (P=0.001). Similar findings were obtained changing cutoffs or considering platelet reactivity as a continuous variable. Genotyping showed the same efficacy between high-dose clopidogrel and prasugrel in the 18 (56.3%) CYP2C19*2 noncarriers (HTPR in 12.5% versus 0, P=0.274), whereas it was significantly worse in the 14 (43.7%) carriers (HTPR in 43.7% versus 0, P=0.003). HTPR is successfully abolished by therapy with prasugrel irrespective of CYP2C19 genotype. Conversely, high-dose clopidogrel can address HTPR only in CYP2C19*2 noncarriers. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01465828.

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A Trial of Intranasal Corticosteroids to Treat Childhood OSA Syndrome.

Intranasal corticosteroids (INCS) are frequently used to treat OSA syndrome (OSAS) in children. However, their efficacy has not been rigorously tested. Do INCS result in improved OSAS symptoms, polysomnography findings, behavior, and quality of life compared with placebo? In this randomized, double-blind, placebo-controlled trial, children with OSAS aged 5 to 12 years (N = 134) were randomized 2:1 to receive 3 months of INCS or placebo. Children in the INCS arm were then re-randomized to receive 9 months of INCS or placebo. Polysomnography, symptoms, and neurobehavioral findings were measured at baseline, 3 months, and 12 months. The primary outcome was change in obstructive apnea hypopnea index (OAHI) at 3 months, available for 122 children. The secondary outcome was OAHI change at 12 months, available for 70 children. Median (interquartile range) age and OAHI at baseline for the entire group were 7.9 (6.3 to 9.9) years and 5.8 (3.6 to 9.7) events per hour. OAHI changes at 3 months (-1.72 [-3.91 to 1.92] events per hour) and 12 months (-1.2 [-4.22 to 1.71] events per hour) were not different between the two groups (P = not significant). OSAS symptoms and neurobehavioral results did not differ between the INCS and placebo groups at 3 and 12 months. The 38 children who received INCS for 12 months reported a significant OAHI decrease from 7.2 (3.62 to 9.88) events per hour to 3.7 (1.56 to 6.4) events per hour (P = .039). In children with OSAS, treatment with INCS did not result in significant polysomnography, neurobehavioral, or symptom changes at 3 and 12 months of treatment. Twelve months of INCS treatment resulted in a statistically significant but not clinically relevant OAHI reduction. ClinicalTrials.gov; No.: NCT02180672; URL: www. gov.

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Effect of diclofenac suppository on tramadol consumption in posthysterectomy pain.

To determine reduction in dose of tramadol and side effects in posthysterectomy patients on addition of diclofenac on rectal suppository. Randomized double blinded placebo controlled study. The Aga Khan University Hospital, Karachi, Pakistan, from August 2004 to January 2006. Seventy ASA I and II females, aged 20 and above, who underwent elective abdominal hysterectomy, were included in this study. Patients received identical looking suppository of either 100 mg diclofenac sodium or placebo after induction of anaesthesia and then 12 hourly for 24 hours. General anaesthesia was standardized and tramadol was given by patient controlled intravenous analgesia delivery system in the recovery. The mean dose + SD of tramadol used in first 24 hours was found to be 317 +153 mg in the placebo-tramadol group compared to 258 +192 mg in the diclofenac-tramadol group (p = 0.15, 95% CI = 1.24 to -1.34, 6.63). Seventeen (49 %) patients in the placebo-tramadol group and 14 (40%) in the diclofenac-tramadol group used rescue analgesia (p=0.47). Sedation score was similar in both the groups and there was no difference in the incidence of nausea and vomiting and use of antiemetics between the groups. This study did not show any reduction in tramadol consumption, given via patient controlled intravenous analgesia when rectal suppository of 100 mg diclofenac was added.

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Are there differences in the symptoms that respond to a selective serotonin or norepinephrine reuptake inhibitor?

We examined two previously published studies comparing a norepinephrine (NE) selective agent, reboxetine, and a serotonin (5-HT) selective agent, fluoxetine, to determine if these agents have different effects on individual depressive symptoms. Both studies were 8-week, double-blind, comparison studies of men and women with DSM III-R major depression. Within-group effect sizes for individual symptom change on the Hamilton Depression Rating Scale (HAMD) were determined in the observed case samples and in patients for whom the symptom was relatively severe at baseline. We required that any significant differences in one sample be cross-validated in the second. Two hundred fifty-three subjects in study I and 168 subjects in study II were randomized to reboxetine or fluoxetine. In both samples, depressed mood, decreased interest, and psychic anxiety had the greatest change. Effect sizes for all HAMD symptoms were similar for the two drugs. No difference between groups in one sample was replicated in the second. Among subjects with severe symptoms, no significant differences were cross-validated. Reboxetine and fluoxetine appear to have similar effects on depressive symptoms. These data suggest that NE and 5-HT selective antidepressant drugs act through the same final common pathway and challenge the belief that symptom differences are useful for antidepressant selection.

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Duration of dual antiplatelet therapy in patients treated with percutaneous coronary intervention for coronary chronic total occlusion.

The duration of dual antiplatelet therapy (DAPT) after drug-eluting stent implantation in coronary chronic total occlusion (CTO) remains unclear. We retrospectively analyzed a total of 512 patients treated with percutaneous coronary intervention (PCI) in the Samsung Medical Center CTO registry. Patients were separated into ≤ 12-month (199, 38.9%) vs. > 12 month (313, 61.1%) based on DAPT duration with aspirin and clopidogrel. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE) during follow-up. Median follow-up duration was 67 (interquartile range: 51-84) months. MACCE occurred in 43 patients (21.6%) in the ≤ 12-month and 55 patients (17.6%) in the > 12-month groups. In the propensity-matched population, the rate of MACCE did not differ significantly between the ≤ 12-month and > 12-month group (19.4% vs. 18.8%; hazard ratio [HR], 0.95; 95% confidential interval [CI], 0.52-1.76, p = 0.88). Moreover, moderate or severe bleeding according to BARC criteria (type 2, 3 or 5) was also similar between the ≤ 12-month and > 12-month group (2.5% vs. 1.9%; HR, 1.00; 95% CI, 0.20-4.96, p = 0.99). Among patients treated with PCI for CTO, DAPT with durations of ≤ 12-month showed similar long-term clinical outcomes compared to > 12-month DAPT.

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Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial.

Very short mandatory dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) with a drug-eluting stent may be an attractive option. To test the hypothesis of noninferiority of 1 month of DAPT compared with standard 12 months of DAPT for a composite end point of cardiovascular and bleeding events. Multicenter, open-label, randomized clinical trial enrolling 3045 patients who underwent PCI at 90 hospitals in Japan from December 2015 through December 2017. Final 1-year clinical follow-up was completed in January 2019. Patients were randomized either to 1 month of DAPT followed by clopidogrel monotherapy (n=1523) or to 12 months of DAPT with aspirin and clopidogrel (n=1522). The primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months, with a relative noninferiority margin of 50%. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding. Among 3045 patients randomized, 36 withdrew consent; of 3009 remaining, 2974 (99%) completed the trial. One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, -1.34% [95% CI, -2.57% to -0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, -0.55% [95% CI, -1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, -1.13% [95% CI, -1.84% to -0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority). Among patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority. These findings suggest that a shorter duration of DAPT may provide benefit, although given study limitations, additional research is needed in other populations. ClinicalTrials.gov Identifier: NCT02619760.

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Raising the decontamination level for thyroid hormone ingestions.

Ninety-two pediatric cases (age < or = 6 years) of acute thyroid hormone ingestions that were reported over a 20-month period to one American Association of Poison Control Centers (AAPCC)-certified regional poison center were reviewed to determine whether significant toxicity in pediatric patients is associated with acute ingestions of < or = 5 mg levothyroxine (T4) equivalent of thyroid hormone and the highest-tolerated milligram-per-kilogram dose. Parameters evaluated included patient weight, amount ingested, drug preparation, treatment type, outcome, management site, and relevant comments. Eight patients had mild symptoms requiring no specific medical intervention and there was no correlation between the amount ingested and symptoms observed. The maximum T4 dose ingested without gastrointestinal decontamination was 0.13 mg/kg (2 mg). A literature review was also conducted. Only one case of moderate toxicity with a dose of less than 5 mg T4 equivalent was found in the literature review. Significant toxicity is not expected with ingestions of less than or equal to 5 mg T4 equivalent of thyroid hormone.

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Broxaterol (Z.1170), a new oral beta 2-agonist compared with salbutamol.

The bronchodilating activity and tolerability of a single 0.5-mg oral dose of broxaterol (Z.1170) were evaluated in 18 patients with reversible bronchial obstruction. Salbutamol 4.0 mg and placebo were used as controls. The study design was double-blind within patients. The forced expiratory volume in 1 s (FEV1), pulse rate, and blood pressure were measured immediately before and 0.5, 1, 2, 3, 4, 5, and 6 h after each treatment. At the same time clinical controls were made to detect the possible presence of side effects. Both broxaterol and salbutamol caused significant increases in FEV1 until the 5th hour as compared to baseline values and until the 2nd hour as compared to placebo. No significant difference was reported between the effects of broxaterol and those of salbutamol at all the times considered. The tolerability of broxaterol was good, as was that of salbutamol. The pulse rate and blood pressure did not show any significant clinical variations. The side effect reported most frequently was tremor.

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Currently used doses of omeprazole in Zollinger-Ellison syndrome are too high.

The efficacy of omeprazole increases during the first few days of administration, suggesting that long-term maintenance dose requirements in patients with Zollinger-Ellison syndrome may be lower than those initially established by upward titration. Long-term maintenance doses of omeprazole were prospectively reduced in 37 patients who had been taking omeprazole for 22 +/- 4 months. Successful reduction was defined as reduction to 20 mg once or twice daily with an absence of symptoms, endoscopy without evidence of active acid-peptic disease, and a gastric acid output of < 10 mEq/h. Sixty-eight percent of patients (25/37) were successfully reduced to 20 mg of omeprazole once (18/24) or twice daily (7/13). Ninety-five percent of patients (20/21) without multiple endocrine neoplasia type I, severe gastroesophageal reflux disease, or previous partial gastrectomy had safe reductions of doses. It is concluded that the currently used omeprazole maintenance doses in patients with Zollinger-Ellison syndrome are too high and advocated that the initial dose still be established by acute daily upward titration followed by gradual reduction once control of acid output has been achieved.

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[Treatment of affective disorders with clonazepam].

On the basis of the hypothetical utility of clonazepam (CLN) for the treatment of affective disorders, by means of previous references and etiopathogenic hypothesis like the Kindling phenomenon we have been developing a study in order to evaluate that usefulness and efficacy which, includes 32 patients with affective disorders; 23 of them with a diagnosis of bipolar disorder (manic) the greatest part of the subjects had been previously treated with lithium antidepressants or neuroleptics, and clonazepam was introduced because of an inadequate response, treatment intolerance or searching for a specific effect. Our results suggest a prevalence of partial and good responses (85%) The same in the objective evaluations as in the subjective ones being the levels of response higher than in previous treatments. The study supports the use of CLN in the treatment of patients who suffer from affective disorders, particularly in hypomanic episodes.

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Methotrexate vs azathioprine in second-line therapy of sarcoidosis.

Steroids remain the first-choice therapeutic in sarcoidosis; however, long-term use is associated with toxicity. Evidence defining the best second-line therapeutic is currently lacking. The aim of this study was to compare the effect of methotrexate and azathioprine on prednisone tapering, pulmonary function, and side effects in the second-line treatment of sarcoidosis. An international retrospective cohort study was performed, reviewing all patients with sarcoidosis who started methotrexate or azathioprine until 2 years after initiation or discontinuation. A linear mixed model with FEV1, vital capacity (VC), diffusing capacity of lung for carbon monoxide (DLCO), and prednisone dose changes over time as end points was used. Side effects were compared with χ2 tests. Two hundred patients were included, of whom 145 received methotrexate and 55 azathioprine. Prednisone daily dose decreased a mean of 6.32 mg/y (P < .0001) while on therapy, with a similar steroid-sparing capacity for methotrexate and azathioprine. Of all patients completing 1 year of therapy, 70% had a reduction in daily prednisone dose of at least 10 mg. FEV1 showed a mean increase of 52 mL/y (P = .006) and VC of 95 mL/y (P = .001) in both treatment groups. DLCO % predicted increased, with a mean of 1.23%/y (P = .018). There were more patients with infections in the azathioprine group (34.6% vs 18.1%, P = .01), but no differences regarding other side effects. This retrospective study comparing the effect of second-line therapy in sarcoidosis shows that both methotrexate and azathioprine have significant steroid-sparing potency, a similar positive effect on lung function, and comparable side effects, except for a higher infection rate in the azathioprine group.

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Hodgkin's disease in 82 Turkish children diagnosed over a 10-year period: epidemiological, clinical, and histopathologic features and prognosis with prolonged chemotherapy.

In this study, 82 Turkish children with Hodgkin's disease (HD) between 1 and 14 years of age and diagnosed over a 10-year period were evaluated retrospectively. More than half of the patients (54%) presented with advanced stages of HD. Mixed cellularity (MC) was the most frequent (56.1%) histopathologic type, which was followed by nodular sclerosing (NS, 18.3%) in frequency. None of the patients received radiotherapy as initial treatment. In 67 children the COPP regimen alone and in 15 the ABVD regimen alternating with COPP were started, to be given as a total of 12 courses. In the patients who presented with stage I-II HD the overall survival (OAS) rate and 5-year event free survival (EFS) rate were 92.3% and 77.8%, respectively. In the patients with advanced disease (stage III-IV) OAS and 5-year EFS were estimated to be 89.5% and 67.4%, respectively. No serious toxicity of chemotherapy was detected during the follow-up. In this group, clinical, epidemiological and histopathologic features of the disease showed a special pattern close to the type I pattern of HD. Regarding the survival rules and occurrence of low toxicity in our patients, results of prolonged chemotherapy alone seem to be encouraging in most of the children with HD. However, the follow-up duration is not yet sufficient to declare a clear conclusion related to the late complications.

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Repeated adjuvant chemotherapy with phenylalanine mustard or 5-fluorouracil, cyclophosphamide, and prednisone with or without radiation, after mastectomy for breast cancer.

172 patients who had had mastectomy for breast cancer were treated by repeated adjuvant chemotherapy, either with phenylalanine mustard (P.A.M.) or a combination of cyclophosphamide, 5-fluorouracil, and prednisone (C.F.P.) with and without radiotherapy. Tumours recurred significantly more frequently and mortality tended to be higher in P.A.M.-treated patients than in patients on other treatment. The interval between surgery and disease recurrence was significantly shorter for P.A.M.-treated premenopausal but not postmenopausal patients than for patients of equivalent menstrual status treated with C.F.P. with or without radiation. The associations in premenopausal patients between the mode of treatment and both survival and the disease-free interval were significant before and after adjustment for variations between the treatment groups in the number of involved lymph nodes and the size of the primary tumour.

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Cytochrome P450 CYP 2C19*2 Associated with Adverse 1-Year Cardiovascular Events in Patients with Acute Coronary Syndrome.

The cytochrome P450 (CYP450) 2C19 681 genotypes affect the antiplatelet activity of clopidogrel. We investigated the correlation of CYP 2C19 681G > A mutation with clopidogrel resistance (CR). Additionally, we studied the effect of CR on clinical prognosis of patients with acute coronary syndrome (ACS). One hundred ten ACS patients undergoing percutaneous coronary intervention, who were followed-up for 1 year, were included in the study. The patients were co-administered aspirin 100 mg/d and clopidogrel 75mg/d following a loading dose of 300 mg. CR was assessed on the basis of polymorphism observed in the CYP2C19 subgroup. Patients in GG genotype group exhibited greater inhibition of platelet aggregation than patients in GA and AA genotype groups (16.2 ± 10.1%; 10.2 ± 9.9%; 8.0 ± 5.9%, respectively, p < 0.01). CYP2C19 681GG genotype group was associated with lower CR than CYP2C19 681A allele (GA + AA) group (9/59 vs. (12+5)/51; p = 0.009). Over a follow-up of 12 months, the incidence of recurrent angina, acute myocardial infarction, and intra-stent thrombosis in CYP2C19 681 GG carriers was significantly lower than that in CYP2C19 681A allele (GA + AA) group (2/59 vs. 8/51, 1/59 vs. 6/51, 0 vs. 4/51, respectively, p < 0.05). CYP 2C19*2 is associated with reduced clopidogrel antiplatelet activity and might be an important marker for poor prognosis of ACS.

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Simvastatin treatment on postprandial hypertriglyceridemia in type 2 diabetes mellitus patients with combined hyperlipidemia.

Recent studies have shown that statins are effective in reducing fasting low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels. However, it remains unknown if treatment with statins also lowers daily postprandial triglyceride concentrations, which may promote atherogenesis in type 2 diabetes subjects. Forty-one subjects with type 2 diabetes and combined hyperlipidemia who had stable glycemic control were randomly assigned to take simvastatin 20 mg (n = 27) or a placebo (n = 14) once daily for 12 weeks. The medication dosage was doubled after 4 weeks if a subject's LDL-C was not less than 130 mg/dL. Among these participants, 24 subjects (15 on simvastatin and 9 on placebo) agreed to take a meal tolerance test with isocaloric mixed meals (carbohydrate, 52%; fat, 33%, and protein, 15% of the daily caloric intake) and daytime hourly blood sampling from 8 AM to 4 PM. Simvastatin treatment reduced the fasting total cholesterol level from 237 +/- 5 to 178 +/- 6 mg/dL (-25%), the LDL cholesterol level from 150 +/- 6 to 87 +/- 5 mg/dL (-40%), and raised high-density lipoprotein-cholesterol (HDL-C) level from 36 +/- 2 to 40 +/- 2 mg/dL (+11%) (all P <.001). Fasting and daily ambient triglyceride concentrations from 8 AM to 4 PM decreased significantly in response to simvastatin administration (P <.001), but not to the placebo (P =.305). Simvastatin treatment not only decreased total cholesterol and LDL-C levels and increased HDL-C levels effectively, it also decreased fasting, as well as daily postprandial triglyceride concentrations, but had no effect on glycemic control in type 2 diabetes subjects with combined hyperlipidemia.

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Effect of intravenous magnesium infusion on salbutamol-induced bronchodilatation in patients with asthma.

In vitro experimental data show that magnesium increases beta-receptor affinity to agonists. We studied the effect of a mild increase in serum magnesium level on the bronchial dose-response curve to salbutamol in six patients with asthma (age 54 +/- 3.6 years, FEV1 49.2 +/- 4.9 per cent of predicted), with a normal serum magnesium level, in a double blind placebo-controlled design. The salbutamol dose-response curve was obtained on two separate days, starting 30 min after an intravenous infusion of saline or MgSO4 (20 mg/kg over 10 min, followed by 10 mg/kg/h). The baseline FEV1 values and the values after 30 min infusion on the two test days were not significantly different. During MgSO4 infusion, the serum magnesium level increased significantly from 0.86 +/- 0.01 to 1.31 +/- 0.19 mmol/litre after 30 min and 1.29 +/- 0.17 mmol/litre at the end of the study. FEV1 values after salbutamol were significantly higher during MgSO4 than during saline infusion at the low doses of salbutamol: 1480 +/- 253 vs. 1368 +/- 212 ml, P < 0.05, after 5 micrograms, and 1596 +/- 585 vs. 1378 +/- 532 ml, P < 0.01, after 10 micrograms of salbutamol. The maximum increase in FEV1 obtained after the maximum dose of salbutamol (400 micrograms) was not significantly different during saline and MgSO4 infusion. In conclusion, a mild sustained increase in serum magnesium level increases the bronchodilating effect of low doses of salbutamol, possibly through an increased beta-receptor affinity. There was no effect on the maximum bronchodilating effect of salbutamol.

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Exploring patients' reasons for discontinuance of heart medications.

Despite the importance of secondary prevention, nonadherence rates for patients with myocardial infarction (MI) range from 13% to 60% for prescribed, evidence-based medicines. Although rates and consequences of discontinuance vary for different medications, the existing literature provides little insight into reasons for discontinuance. To address this gap, we explored clopidogrel and cholesterol-lowering therapy (CLT) discontinuance after an MI to understand patients' reasons for stopping these 2 medications. In this qualitative descriptive study, 2 groups of patients who stopped a heart medication-either clopidogrel or CLT-were recruited from a prospective MI registry. Patients who discontinued CLT (n = 29) or clopidogrel (n = 11) were interviewed within 18 months of hospitalization. Patients were recruited and interviewed until data saturation was achieved. The Health Belief Model was used as an organizing framework in analyzing and coding the narrative data. The codes were then summarized for each group and compared to identify similarities and differences in reasons for CLT and clopidogrel discontinuance. The most common reason for CLT discontinuance was adverse effects that were painful and interfered with daily life. Less common reasons for discontinuance were prescription confusion, cost, mistrust in medicines/healthcare system, and preference for alternative therapies. Reasons for clopidogrel discontinuance were duration confusion, adverse effects, and cost. Although doctors stopped patients' clopidogrel in preparation for surgery, doctors conceded to discontinuance of CLT for patients who experienced adverse effects after trying 2 to 3 different CLTs. Patients who discontinued CLT were more likely to believe that they did not need the treatment than do patients who discontinued clopidogrel. Clinicians should be aware that reasons may vary across patients and medication class for prematurely stopping therapy; thus, proactive interventions should be targeted to address these differences. Identifying at-risk patients for targeted interventions to prevent premature cardiac medication discontinuation is vital.

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Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin.

Inflammation contributes to the pathophysiology of major depressive disorder (MDD), and anti-inflammatory strategies might therefore have therapeutic potential. This trial aimed to determine whether adjunctive aspirin or rosuvastatin, compared with placebo, reduced depressive symptoms in young people (15-25 years). YoDA-A, Youth Depression Alleviation with Anti-inflammatory Agents, was a 12-week triple-blind, randomised, controlled trial. Participants were young people (aged 15-25 years) with moderate to severe MDD (MADRS mean at baseline 32.5 ± 6.0; N = 130; age 20.2 ± 2.6; 60% female), recruited between June 2013 and June 2017 across six sites in Victoria, Australia. In addition to treatment as usual, participants were randomised to receive aspirin (n = 40), rosuvastatin (n = 48), or placebo (n = 42), with assessments at baseline and weeks 4, 8, 12, and 26. The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. At the a priori primary endpoint of MADRS differential change from baseline at week 12, there was no significant difference between aspirin and placebo (1.9, 95% CI (- 2.8, 6.6), p = 0.433), or rosuvastatin and placebo (- 4.2, 95% CI (- 9.1, 0.6), p = 0.089). For rosuvastatin, secondary outcomes on self-rated depression and global impression, quality of life, functioning, and mania were not significantly different from placebo. Aspirin was inferior to placebo on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) at week 12. Statins were superior to aspirin on the MADRS, the Clinical Global Impressions Severity Scale (CGI-S), and the Negative Problem Orientation Questionnaire scale (NPOQ) at week 12. The addition of either aspirin or rosuvastatin did not to confer any beneficial effect over and above routine treatment for depression in young people. Exploratory comparisons of secondary outcomes provide limited support for a potential therapeutic role for adjunctive rosuvastatin, but not for aspirin, in youth depression. Australian New Zealand Clinical Trials Registry, ACTRN12613000112763. Registered on 30/01/2013.

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Drug treatment of REM sleep behavior disorder: the use of drug therapies other than clonazepam.

REM sleep behavior disorder (RBD) is characterized by loss of the normal muscle atonia during REM sleep associated with disruptive motor activity related to the acting out of dreams. There is frequently injury to the patient or bed partner, and treatment is usually required. Clonazepam has been the first-line therapy for many years, with 2 large case series reporting efficacy with few side effects in the majority of patients. However, long-acting hypnotics in the elderly or those with cognitive impairment can be associated with adverse events especially unacceptable daytime sedation, confusion, and exacerbation of existing sleep apnea. We reviewed 39 patients with confirmed RBD who were treated within our regional sleep center, assessing both efficacy and side effects of drug therapies. Adverse effects were reported by 58% of the patients using clonazepam, with 50% either discontinuing the drug or reducing the dose. This prompted us review the side effects of clonazepam in detail and to look for alternative therapies. We report several novel and effective therapies, in particular zopiclone, in a series of patients under long-term follow-up for RBD. There are alternatives to clonazepam therapy for RBD which can be as effective and may be better tolerated.

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Influence of CYP3A4 and CYP3A5 polymorphisms on tacrolimus and sirolimus exposure in stable kidney transplant recipients.

Polymorphisms in genes encoding for drug-metabolizing enzymes and drug transporters are among multiple factors that modulate the pharmacokinetic variability of tacrolimus (TAC) and sirolimus (SRL). This study aimed to evaluate the influence of single nucleotide polymorphisms (SNPs) on TAC and SRL dose-adjusted concentrations (C0/D) in stable kidney transplant recipients. This is an exploratory and prospective study, which includes 46 stable kidney transplant recipients. These patients were monitored from the 3rd to the 24th month after transplantation. The SRL group consisted of 25 patients receiving TAC, prednisone (PRED), and mycophenolate sodium (MPS), which were converted from TAC to SRL at 3rd month after transplantation. The TAC group consisted of 21 patients who underwent treatment with TAC, PRED, and MPS. Both groups were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T), CYP2C8 rs10509681 (c.1196A>G) and ABCB1 rs1045642 (c.3435C>T), rs1128503 (c.1236C>T), and rs2032582 (c.2677G>T/A) polymorphisms. In the TAC group, CYP3A4 rs2242480 A allele carriers were associated with lower TAC C0/D. For CYP3A5 rs15524 SNP, C0/D was higher among patients carrying TT genotype when compared with CT and CC genotype carriers in the SRL and, more consistently, in the TAC groups. For ABCB1 rs1045642 SNP, TT genotype was associated with reduced SRL C0/D, but only at month 15. CYP3A4 rs2242480 and CYP3A5 rs15524 SNPs resulted in significant changes in SRL and TAC C0/D at different times after transplantation.

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Adverse effects of methylphenidate on the reproductive axis of adolescent female rats.

To examine the effects of chronic methylphenidate use on the reproductive axis of adolescent female rats. Controlled prospective study. University research laboratory. Twenty prepubertal female Sprague Dawley rats. Subcutaneous implantation of drug-filled Alzet minipumps (Durect Corporation, Cupertino, CA) for infusing methylphenidate (450 microg/d, treated) or physiological saline (control) for 4 weeks. Estrous cyclicity was checked from 3 weeks of pump implantation till the termination of the experiments. Animals were killed after 4 weeks of treatment. Estrous cyclicity, pituitary and peripheral FSH and LH, serum estrogen and progesterone, ovarian histology, and immunocytochemistry for localizing growth differentiation factor-9 and activin receptors-I. Compared with the control group, the treated animals exhibited the following: [1] poor vaginal opening and erratic estrous cyclicity; [2] undeveloped, disrupted, or prematurely luteinized ovarian follicles; [3] absence of growth differentiation factor-9 and of activin receptors I and IB in the oocyte; and [4] high levels of LH in the pituitary. Chronic methylphenidate administration during adolescence perturbs pubertal onset, adversely affects maturation of the female reproductive axis by retarding pituitary LH release, and adversely affects ovarian folliculogenesis. These novel findings may have significant clinical implications in evaluating the effects of methylphenidate abuse on adolescent health.

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[Clinical evaluation of lenampicillin in the treatment of superficial suppurative skin and soft tissue infection. A double-blind study comparing amoxicillin].

A double-blind controlled clinical study between lenampicillin (LAPC), a newly developed oral ampicillin (ABPC) prodrug, and amoxicillin (AMPC) was conducted for the treatment of suppurative skin and soft tissue infection as grouped in 6 disease types. LAPC or AMPC were orally administered at a daily dose of 1,000 mg, in 4 equally divided doses. Each group was treated for 14 days. The results indicated that LAPC was equal to AMPC in evaluations of effectiveness and usefulness, although incidence of severe side effects was slightly lower in LAPC. The number of cases studied was 235 (115 in the LAPC group, 120 in the AMPC group). Among these, 10 patients (4 in LAPC, 6 in AMPC) were excluded and 12 patients (5 in LAPC, 7 in AMPC) dropped out. Final global improvement rating was evaluated in 213 patients (106 in LAPC, 107 in AMPC). General usefulness rating was evaluated in 215 patients (106 in LAPC, 109 in AMPC), and overall safety rating was evaluated in 231 patients (115 in LAPC, 116 in AMPC). Final global improvement rating of LAPC was, "cured", 55.7% and "cured" and "remarkably improved", 79.2%. The rate increased to 88.7% when "improved" was included. On the other hand, in the AMPC group, "cured" was 50.5%, and "cured" and "remarkably improved" was 76.6%. The rate increased to 91.6% when "improved" was included. No significant difference was found between the 2 drug groups. In overall safety rating of LAPC, "safe" was 93.9%, while in the AMPC group, "safe" was 94.0%. No significant difference was found between the 2 drug groups. Side effects were noted in 2 of 115 patients (1.7%) among the LAPC group and in 5 of 116 patients (4.3%) among the AMPC group. Incidence of severe side effects was slightly lower in LAPC (P less than 0.1). General usefulness rating of LAPC was, "remarkably useful", 56.6% and the rate increased to 86.8% when "useful" was included. In the AMPC group, "remarkably useful" was 51.4%, and increased to 84.4% when "useful" was included. No significant difference was found between the 2 drug groups.

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Non steroidal anti-inflammatory drugs (NSAID) and Aspirin for preventing colorectal adenomas and carcinomas.

This review was split in 2012 and the review question was to be addressed according to three new protocols: (See: http://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010267.pub2; http://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010291.pub2; http://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010325.pub2). These titles were withdrawn at the protocol stage in 2020 as the authors did not make any progress on the reviews. This original review will no longer be updated and may be superseded by new titles hosted by Cochrane Gut in the future. There is evidence from experimental animals studies, prospective and retrospective observational studies that nonsteroidal anti-inflammatory drugs (NSAIDS) may reduce the development of sporadic colorectal adenomas (CRAs) and cancer (CRC) and may induce the regression of adenomas in familial adenomatous polyposis (FAP). To conduct a systematic review to determine the effect of NSAIDS for the prevention or regression of CRAs and CRC. Randomized controlled trials (RCTs) up to September 2003 were identified. NSAIDS and aspirin (ASA) were the interventions. The primary outcomes were the number of subjects with at least one CRA, the change in polyp burden, and CRC. The secondary outcome was adverse events. Two reviewers independently extracted data and assessed trial quality. Dichotomous outcomes were reported as relative risks (RR) with 95% confidence intervals (CI). The data were combined with the random effects model if clinically and statistically reasonable. Nine trials with 150 familial adenomatous polyposis (FAP) and 24,143 population subjects met the inclusion criteria. The interventions included sulindac, celecoxib, or aspirin (ASA). From the combined results of three trials, significantly fewer subjects in the low dose ASA group developed recurrent sporadic CRAs [RR 0.77 (95% CI 0.61, 0.96), (NNT 12.5 (95% CI 7.7, 25)] after one to three years. In another three trials, phenotypic FAP subjects that received sulindac or celecoxib had a greater proportional reduction (range: 11.9% to 44%) in the number of CRAs compared to those in the control group (range: 4.5% to 10%). There was no significant difference for the outcomes of CRC or adverse events in any of the trials. There was evidence from three pooled RCTs that ASA significantly reduces the recurrence of sporadic adenomatous polyps after one to three years. There is evidence from short-term studies to support regression, but not elimination or prevention of CRAs in FAP.

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Rationale for the Assessment of Metoprolol in the Prevention of Vasovagal Syncope in Aging Subjects Trial (POST5).

Vasovagal syncope (VVS) is a common problem associated with a poor quality of life, which improves when syncope frequency is reduced. Effective pharmacological therapies for VVS are lacking. Metoprolol is a β-adrenergic receptor antagonist that is ineffective in younger patients, but may benefit older (≥40 years) VVS patients. Given the limited therapeutic options, a placebo-controlled clinical trial of metoprolol for the prevention of VVS in older patients is needed. The POST5 is a multicenter, international, randomized, placebo-controlled study of metoprolol in the prevention of VVS in patients ≥40 years old. The primary endpoint is the time to first recurrence of syncope. Patients will be randomized 1:1 to receive metoprolol 25 to 100 mg BID or matching placebo, and followed up for 1 year. Secondary end points include syncope frequency, presyncope, quality of life, and cost analysis. Primary analysis will be intention to treat, with a secondary on-treatment analysis. A sample size of 222, split equally between the groups achieves 85% power to detect a hazard rate of 0.3561 when the event rates are 50% and 30% in the placebo and metoprolol arms. Allowing for 10% dropout, we propose to enroll 248 patients. This study will be the first adequately powered trial to determine whether metoprolol is effective in preventing VVS in patients ≥40 years. If effective, metoprolol may become the first line pharmacological therapy for these patients.

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